Classifications

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  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
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  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
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  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
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  • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
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  • A61K8/0241—Containing particulates characterized by their shape and/or structure
  • A61K8/0245—Specific shapes or structures not provided for by any of the groups of A61K8/0241
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  • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
  • A61K8/34—Alcohols
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  • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
  • A61K8/36—Carboxylic acids; Salts or anhydrides thereof
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  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
  • A61K8/42—Amides
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  • A61K8/92—Oils, fats or waxes; Derivatives thereof, e.g. hydrogenation products thereof
  • A61K8/922—Oils, fats or waxes; Derivatives thereof, e.g. hydrogenation products thereof of vegetable origin
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  • A61K8/927—Oils, fats or waxes; Derivatives thereof, e.g. hydrogenation products thereof of insects, e.g. shellac
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  • A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
  • A61K8/98—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution of animal origin
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  • A61K2800/412—Microsized, i.e. having sizes between 0.1 and 100 microns
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  • A61K2800/65—Characterized by the composition of the particulate/core
  • A61K2800/652—The particulate/core comprising organic material

Definitions

• compositions and foamab!e compositions such as those comprising waxes, emollients, foam adjuvants and/or active agents, and methods for preparing and using them.
• Acne is a common category of skin disorders which afflicts many people. The prevalence of adult acne is about 3% in men and between about 1 1% and 12% in women. Moderate to severe acne is observed in about 14% of acne patients. There are various types of acne recognized in the field, including, for example: acne vulgaris and acne congiobata.
• Acne vulgaris (cystic acne or simply acne) is generally characterized by areas of skin with seborrhea (scaly red skin), comedones (blackheads and whiteheads), papules (pinheads), pustules (pimples), nodules (large papules) and/or possibly scarring.
• Acne vulgaris may affect the face, the upper part of the chest, and the back, among other topical areas. Severe acne vulgaris is inflammatory, but acne vulgaris can also manifest in non-inflammatory forms.
• Acne congiobata is a severe form of acne and may involve many inflamed nodules that are connected under the skin to other nodules. Acne congiobata often affects the neck, chest, arms, and buttocks.
• Mild acne vulgaris is characterized by the presence of few to several papules and pustules, but no nodules. Patients with moderate acne typically have several to many papules and pustules, along with a few to several nodules. With severe acne vulgaris, patients typically have numerous or extensive papules and pustules, as well as many nodules.
• Treatment for moderate or severe acne typically requires systemic antibiotics like tetracycline and its derivatives (e.g., minocycline and doxycycline) that are given orally or by injection.
• systemic antibiotics like tetracycline and its derivatives (e.g., minocycline and doxycycline) that are given orally or by injection.
• tetracycline and its derivatives e.g., minocycline and doxycycline
• oral tetracycline therapy may induce hyperpigmentation in many organs, including nails, bone, skin, eyes, thyroid, visceral tissue, oral cavity (teeth, mucosa, alveolar bone), sc!erae and heart valves.
• Skin and oral hyperpigmentation have been reported to occur regardless of the amount of time or drug administered, whereas other tissue hyperpigmentation have been reported to occur upon prolonged administration.
• Skin hyperpigmentation includes diffuse hyperpigmentation as well as over sites of scars or injury.
• Oral treatments may not be effective against all forms of acne, such as non-inflammatory acne.
• Oral tetracyclines are also not indicated for pregnant women or nursing mothers due to teratogenic effects.
• An example of a commercially available oral tetracycline-based treatment for acne is SOLODYN ® It is indicated to treat only inflammatory lesions of non-nodular moderate to severe acne vulgaris in patients 12 years of age or older.
• Adverse side effects from the use of SOLODYN ® include, inter alia, diarrhea, dizziness, lightheadedness, and nausea, in addition to allergic reactions, bloody stool, blurred vision, rectal or genital irritation, and red, swollen, blistered, or peeling skin. Because of these side effects, the Food and Drug
• tetracycline-based antibiotics e.g., for use in treating acne or other indications
• tetracycline-based antibiotics are sensitive to moisture, temperature, and light.
• tetracycline-based antibiotics are highly susceptible to degradation by a wide range of pharmaceutical carriers and excipients that are typically used as solvents and carriers.
• they are often unstable when suspended in emulsion or dissolved in solution.
• formulating useful tetracycline antibiotics, particularly when combined with other active agents such as retinoids, for topical administration requires the identification of a carrier system in which a tetracycline antibiotic remains stable for a sufficiently long period of time for product distribution, storage at a pharmacy, and subsequent therapeutic use by a patient.
• Such a formulation or carrier system should also allow an active agent, e.g., a tetracycline antibiotic, to penetrate into the skin or mucosa whilst avoiding degradation and preventing the active agent from reaching the blood system in significant or substantial amounts to avoid or minimize potential systemic side effects in addition, such a formulation or carrier system should also allow an active agent or combination of agents or the carrier itself to remain physically stable without aggregating, clumping, precipitating or separating, and remain homogeneously distributed. Once such a carrier system has been created for tetracycline antibiotics, it may have application for other stable and unstable active agents.
• an active agent e.g., a tetracycline antibiotic
• Topical composition comprising for e.g. tetracycline antibiotics may be formulated in any form, e.g., as a liquid, gel, ointment, or a foam. Topical composition comprising for e.g. tetracycline antibiotics may also be foamed.
• Foams are an increasingly popular delivery system for topical drugs, and may be a platform whereby tetracycline- based antibiotics remain stable for topical administration.
• Foamable formulations or compositions are typically packaged as a liquid or gel in a pressurized aerosol container together with a propellant, and upon actuation of a valve, the composition is released from the container and forms a foam lattice.
• an aerosol container During use of an aerosol container, it is sometimes desirable to shake the container to homogenize its contents prior to actuation of the valve and formation of the foam. Shaking an aerosol can may enable the user to gauge the presence of liquid contents within the can. Shaking may also improve the formation of foam by aiding its incorporation into the composition e.g. facilitating emulsifying or dissolving the propellant in the composition. Foamable compositions comprising tetracycline-based antibiotics may therefore benefit from being shakable and fiowabie such that they can be expelled from a canister or tube without blocking the valve or tube. There remains a need in the art for improved foamable formulations that further enhance some or all of these properties.
• compositions are carriers and may further comprise one or more therapeutic active agents e.g., tetracycline- based antibiotics ⁇ alone or In combination with other active ingredients and/or excipients).
• the compositions may be formulated in different ways e.g., as a liquid, a foamed liquid, a gel, a foamed gel, an ointment, a foamed ointment, or a foam.
• the compositions disclosed herein may also be foamable.
• the compositions described herein may provide for improved stability and/or shakeabi!ity and/or usability.
• Compositions with new crystal structures and ratios are disclosed.
• Compositions comprising Tmh crystals are provided.
• Compositions comprising Tmh crystals and plates are provided.
• compositions comprising Tmh crystals and plates and spherulites are provided.
• Compositions comprising plates are provided.
• Compositions comprising Tmh crystals for example having higher order crystal structures, may contribute to improved stability and/or also provide for improved shakability.
• Such compositions are, for example, capable of lowering the melting temperature of the sebum and thereby may also provide for improved ability to liquify or dissolve sebum aiding and allowing for opening of pores and facilitating access of the composition into the pores.
• Such compositions can also facilitate skin penetration of active agents into the dermis and epidermis. Without being bound to any theory, such compositions when including tetracycline antibiotics may surprisingly help reduce, minimize or not generate antibiotic resistance.
• compositions may facilitate targeting of drug in the sebaceous gland tetracycline, e.g., helping opening pores and directing drug, e.g., a tetracycline antibiotic into the pilosebaceous unit where P. acnes can reside, which in turn may enhance efficacy and safety and moreover may help prevent resistance arising.
• the technology described herein can have broad application to create formulations with novel Tmh crystals comprising a unique high order wax crystal structure generated through the processes described herein.
• Crystallization may be undesirable and often a reflection on a poor solvent system in contrast, for the formulations provided herein, crystallization may provide beneficial properties. Typically, crystallization is more likely to occur in a solvent that is different from the solute to be crystalized. Yet, crystallization in the formulations provided herein is achieved from a solvent (emollient) that is similar or closely similar to the substance to be crystalized. Such similarity can result in crystals with novel crystal fingerprints that provide advantages and improved properties to the formulation in one or more embodiments, without being bound by any theory, a holding process may contribute to the generation of Tmh crystals and the
• crystallization in the formulations provided herein does not result in a new polymorphic structure but, rather, retains the same polymorphic form, e.g. beta (b) remains beta (b) or beta' (b') remains beta' (b').
• crystallization by a holding process may result in a minor polymorphic structure change in one or more embodiments
• crystallization in the formulations provided herein results in a new microstructure and/or a new crystal fingerprint.
• the Tmh crystal structure formed by a holding process may on average be less dense e.g., with a less concentrated packing arrangement, than the crystal structure comprising spheruiites formed by a continuous heating-cooling process.
• the Tmh crystal structure formed by a holding process may on average occupy a higher percentage of the area measured than the crystal structure comprising spheruiites formed by a continuous heating-cooling process.
• the Tmh crystal structure of the formulations disclosed herein may have a similar or the same density to that of the spheruiites.
• the Tmh crystals on average occupy more space and/or are larger than those of the spheruiites.
• the Tmh crystal structure has stronger and or more interactions (inter-crystal and/or intra-crystal), resulting in a stronger and/or more stable crystal structure.
• the Tmh crystal structure in a formulation disclosed herein displays an increase in enthalpy.
• the Tmh crystal structure results In a significant upward shift in the highest melting point (as measured by DSC) in the carrier and/or in a pharmaceutical composition disclosed herein (e.g., one with minocycline hydrochloride (MCH) and adapalene (ADR) as active pharmaceutical agents in addition to carrier excipients).
• MCH minocycline hydrochloride
• ADR adapalene
• the formulation is a carrier without an active agent in some embodiments the formulation is a composition with one or more therapeutic agents in some embodiments the therapeutic agent is an active pharmaceutical agent, a cosmeceutica!, a cosmetic agent, and/or combinations of one or more of active pharmaceutical agents, cosmeceutical and cosmetic agents in one or more embodiments the compositions can, when applied topically to the skin, facilitate the breakdown and or dissolution of sebum, e.g., by lowering the melting temperature of the sebum. In one or more embodiments the compositions can, when applied topicaliy to the skin, facilitate improving penetration and delivery into rather than through the skin or mucosa or body cavity wall.
• Tmh crystals disclosed herein may be characterized and/or identified by a particular phase transition TM4 temperature, alone or in combination with other properties such as an SRS (i.e., raman) spectra peak with shoulders, and/or a particular FITR wavelength.
• SRS i.e., raman
• composition comprising a tetracycline antibiotic and/or a retinoid, and a wax e.g. hydrogenated castor oil, wherein the wax, such as hydrogenated castor oil, is present in the composition in an amount and form effective to produce a formulation with crystals of a higher melting temperature as compared to those present in formulations prepared by a continuous heating-cooling process.
• the formulation is characterized by an improved fluidity and/or shakability that is maintained for 6 months or more at 25 5 C.
• the formulation comprises a wax other than hydrogenated castor oil.
• the formulation is characterized by an improved fluidity and/or shakability that is maintained for about 3 months, or about, 4 months, or about 5 months, or about 6 months, or about 7 months, or about 8 months, or about 9 months about 10 months, or about, 1 1 months ,or about 12 months, or about 15 months, or about 18 months, or about 21 months, or about 24 months or more at 25 ® C.
• the formulation is characterized by an improved fluidity and/or shakability that is maintained for any one or more of the aforesaid time periods at 5 e C.
• the formulation is characterized by an improved fluidity and/or shakability that is maintained for 3 months or more at 4Q Q G.
• Fig. 1 Difierentia! scanning calorimetry (DSC) thermograms for mode! systems created through stepwise addition of the different formulation components.
• Fig. 2A Different structures in formulations prepared by a continuous heating cooling process and a holding process.
• FIG. 2B Photomicrographs for placebo formulations with 1 .2% hydrogenated castor oil (HCG) prepared by a continuous heating-cooling process or a holding process and kept at 25 °C on day 0.
• HCG hydrogenated castor oil
• Fig. 2G Crystal count, sizes and amounts (%) of different crystal structures in formulations prepared by a continuous heating-cooling process and a holding process.
• FIG. 2D Photomicrographs for placebo formulations with 1 .2% HCO prepared by a continuous heating-cooling process or a holding process and heated from 25 °C to 80 °C on day 0.
• FIG. 2E Photomicrographs for placebo formulations with 2% HCO prepared by a continuous heating-cooling process or a holding process and kept at 25 °C on day 0.
• FIG. 2F Photomicrographs for formulations with 1 .2% HCO comprising MCH+ADP prepared by a holding process followed by the addition of heptane instead of a propellant and kept at 25 °C on day 0.
• FIG. 2G Photomicrographs for collapsed foams from formulations with 1 .2% HCO comprising MCH+ADP prepared by a continuous heating-cooling process or a holding process.
• Fig. 2H DSC thermograms for formulations with 1 .2% HCO comprising MCH+ADP prepared by a continuous heating-cooling process or a holding process and kept at 5 °C for 1 5 and 30 days.
• Fig. 2I DSC thermograms for formulations with 1 .2% HCO comprising MCH+ADP prepared by a continuous heating-cooling process or a holding process and kept at 25 °C for 0, 15 and 30 days.
• Fig. 2J DSC thermograms for formulations with 1 .2% HCO comprising MCH+ADP prepared by a continuous heating-cooling process or a holding process and kept at 40 °C for 0, 15 and 30 days.
• Fig. 2K DSC thermograms for placebo formulations with 1.2% HCO prepared by a continuous heating-cooling process or a holding process and kept at 5 °C, 25 °C or 40 °C for 0 and 15 days.
• Fig. 2L Formulations comprising MCH+ADP with 1 .2% HCO prepared by a continuous heating-cooling process (yellow and grey lines representing two replicates) and a holding process (blue and orange lines representing two replicates), kept at 40 °C and analyzed on day 0 by small angle X-ray scattering.
• Fig. 2M Formulations comprising MCH+ADP with 1 .2% HCO prepared by a continuous heating-cooling process (Blue line) and a holding process (Orange line), kept at 25 °C and analyzed on Day 0 by wide angle X-ray scattering.
• FIG. 2N Figure 2N. Flow point for foam formulations comprising MCH+ADP with 1 .2% HCO manufactured by a continuous heating-cooling process and a holding process, and kept at 40 °C for 0, 15 and 30 days.
• FIG. 3B Photomicrographs of sebum side by side with MAH, a placebo formulation (PCO) and a formulation comprising MCH prepared by a continuous heating-cooling process (MCO) and Oil-in-water emulsion (OIWE) at 25 °C, heated to 35 °C, and held at to 35 °C for 1 minute.
• PCO placebo formulation
• MCH prepared by a continuous heating-cooling process
• OIWE Oil-in-water emulsion
• Fig. 4A Formulation with 1.2% or 2% HCO prepared by a continuous heating cooling process and a holding process and kept at 5 °C, 25 °C and 40 °C for 15 days.
• Fig. 4B Formulation with 1.2% or 2% HCO prepared by a continuous heating- cooling process and 1 .2% HCO prepared by a holding process and kept at 5 °C, 25 °C and 40 °C for 30 days.
• Fig. 5 DSC thermograms for formulations with 1.2% or 2% HCO comprising MCH+ADP, kept at 40°C for 15 days and prepared by three different processes: (1 ) a holding process, (b) holding at 52°C and heating to 65°C, or (c) adding HCO at 22 C.
• Fig. 6A Formulations prepared at different holding temperatures and kept at 25° C (upper panel) or 40 °C (lower panel) on Day 0.
• Fig. 6D Size (pm 2 ) of Tmh crystals and spherulites prepared at different holding temperatures.
• Fig. 6E Relative percentages (by area) of Tmh crystals and spherulites prepared at different holding temperatures.
• Fig. 6F Crystal counts of Tmh crystals and spherulites prepared at different holding temperatures.
• Figs. 6G to 6L Photomicrographs of crystals taken at 50°C In samples manufactured at different holding temperatures.
• Fig. 7A Flow point temperatures for samples stored at 25 °C with different active agent(s) (API) and F!GO levels through storage time.
• Fig. 7B Flow point temperatures for samples stored at 40 °C with different active agent(s) (API) and FICQ levels through storage time.
• API active agent
• Figs. 8A to 8C G' values for samples stored at 25 °C containing MCH+ADP with 2% HCO vs. 1.2% HCO through storage time.
• Fig. 9 G values for samples stored at 40 °C with different active agent(s) (API) through storage time.
• Fig. 10 Viscosity values for samples stored at 25 °C containing MCH and ADR with 2% HCO and with 1.2% HCO through different storage times.
• Fig. 1 Enthalpy change of samples with 2% HCO and 1.2% HCO with and without API prepared by holding process and a formulation prepared by a continuous heating-cooling process.
• Fig. 12A Photomicrograph of Tmh crystals imaged by 50x objective.
• Fig. 12B Photomicrograph of Tmh crystals imaged by 20x objective.
• FIG. 12C Photomicrograph of Tmh crystals imaged by 50x objective at 45°C, following mixture of a sample formulation with acetone.
• Fig. 12D Photomicrograph of Tmh crystals imaged by 50x objective under slow heating (1 °C/min), following mixture of a sample formulation with hexane.
• Fig. 13A Images of glass vials of formulations with different wax ratios stored at 25°C and 40°C.
• Fig. 13B DSC thermograms for upper and lower fractions of a formulation with 1 .2% HCO and 0.1 % beeswax stored at 40°C for 30 days.
• Fig. 13G DSC thermograms for a formulation with 2% HCO and 0.1 % beeswax.
• Fig. 13D DSC thermograms for a formulation with 0.6% HCO and 2% beeswax.
• Fig. 13E DSC thermograms for a formulation with 2% HCO and 2% beeswax.
• Fig. 13F DSC thermograms for a formulation with 2% HCO and 1.2% beeswax.
• Fig. 13G DSC thermograms for a formulation with 1 .2% HCO and 2% beeswax.
• Fig. 13H Images of glass vials of formulations with alternative waxes stored at 25°C and 40°C.
• Fig. 13I DSC thermograms for upper and lower fractions of a formulation with emulsifying wax stored at 40°C for 30 days.
• FIG. 13 J Photomicrograph of upper and lower fractions of a formulation with emulsifying wax.
• Fig. 14A DSC thermograms for a formulation with 23.6% soybean oil and 50% coconut oil.
• Fig. 14B DSC thermograms for a formulation with 50% soybean oil and 23.6% isopropyl myristate oil.
• Fig. 14C DSC thermograms for a formulation with 70% soybean oil and 23.6% coconut oil.
• Fig. 14D DSC thermograms for a formulation with 50% soybean oil and 23.6% MCI oil.
• Fig. 1 5A DSC thermograms for mixtures of different oils and HCO.
• FIG. 1 5B Photomicrographs of a mixture of HCO and coconut oil.
• FIG. 1 5G Photomicrographs of a mixture of HCO and ocfyldodecanol.
• FIG. 1 6A Images of glass vials of formulations with 1 .2% HCO and 2% beeswax prepared by a holding step of 4 hours or about 16 hours (overnight holding) at 25°C and at 40°C.
• Fig. 1 6B DSC thermograms for upper and lower fractions of a formulation with 1 .2% HCO and 2% beeswax prepared by an overnight holding step stored at 40°C for 15 days.
• FIG. 1 6C Photomicrograph of upper and lower fractions of a formulation 1 .2% HCO and 2% beeswax prepared by an overnight holding step stored at 40°C for 15 days and taken at 50°C.
• Fig. 1 7A Full FUR spectra for formulation oils (Coconut oil + soybean oil + mineral oil + cyciomethicone), neat HCO, oils + 1 .2% HCO, and formulations with 1 .2% HCO prepared in a holding process.
• Fig. 1 7B FTIR spectra for formulation’s oils (Coconut oil + soybean oil + mineral oil ⁇ cyciomethicone), neat HCO and oils + 1 .2% HCO.
• Fig. 1 7G FTIR spectra measured through increasing temperatures for formulations with 1 .2% HCO prepared in a holding process vs. a continuous heating- cooling process.
• Fig. 1 7D FTiR spectra measured at 25°C and 50°C for formulations with 1 .2% HCO prepared in a holding process vs. a continuous heating-cooling process.
• Fig. 1 7E FTIR spectra measured at 25°C and 50°C for formulations with 2% HCO prepared in a holding process vs. a continuous heating -cooling process.
• Fig. 17F Frequency of band 1 for formulations with 1 .2% or 2% HCO prepared by a holding process or a continuous heating-cooling process.
• Fig. 18 20x magnification image of minocycline and adapalene with 1 .2% HCO and 2% beeswax prepared by a holding process while heating at 5°C/min.
• Fig. 19 Average release rate results for minocycline and adapalene.
• Fig. 20A SRS (raman) spectra of vehicle batch.
• Fig. 20B SRS spectra of vehicle batch.
• Fig. 21 DSC and shear for batches prepared by different processes.
• Fig. 22A Images observed at 25°C for batch manufactured with holding and shear.
• Fig. 22B 5Gx image of batch manufactured with shear.
• compositions (carriers and/or therapeutic compositions), methods of making them, their applications and uses, e.g., for treating acne in some embodiments the compositions are foamable.
• the therapeutic compositions may comprise one or more active agents e.g., comprising tetracyciine-based antibiotics.
• the compositions may provide superior stability and/or fluidity and/or shakabiiity and/or ability to dissolve sebum.
• the compositions provide superior penetration into the skin in some embodiments the compositions provide improved targeting and or delivery into the pilosebaceous unit. When formulated as a foamable composition and packaged in an aerosol container, characteristics like superior fluidity and/or shakabiiity are additionally advantageous.
• Ail % values are provided on a weight per weight (w/w) basis.
• Various carriers and compositions or formulations are described herein. They are often described for use in a method. A reference to or example of a carrier, composition or formulation for use in one method does not in any way limit the carrier, composition or formulation for use just in that method, but it can be for use in any other method or embodiment described herein.
• the carriers, compositions or formulations described herein are in one or more embodiments provided as carriers, compositions or formulations and are in one or more embodiments provided as a product even where they are described only in relation to their use in a method.
• the term“about” has its usual meaning in the context of pharmaceutical and cosmetic formulations to allow for reasonable variations in amounts that can achieve the same effect, typically plus or minus up to 30%. For example, if an amount of“about 1” is provided, then the amount can be up to 1 .3 or from 0.7. In cases where“about X” will lead to a figure of above 100%, the term in one or more embodiments can be read as reflecting up to 100% by weight less the total of the minimum amount of the other ingredients. Likewise, it will be appreciated by one skilled in the art to the extent X is reduced from that upper level the amounts of the other ingredients are increased appropriately.
• compositions such that where one or more ingredients are varied, successful formulations can still be made even if an amount falls slightly outside the range. Therefore, to allow for this possibility, amounts are qualified by about. In one or more other embodiments, the figures can be read without the term“about.”
• composition(s) and“formulation(s)” can be used interchangeably depending on the context in which they are used as would be appreciated by a person skilled in the art.
• room temperature means 20 °C to 25 °C. In an embodiment it is 20 °C. In an embodiment it is 21 °C. In an embodiment it is 22 °C. in an embodiment it is 23 °C. In an embodiment it is 24 °C. in an embodiment it is 25 °C.
• ambient conditions means room temperature, pressure and humidity. Ambient temperature and room temperature are used interchangeably herein.
• thixotropic means that the formulation shows a decrease in viscosity upon application of a shear force. The structure of the formulation breaks down, leading to a reduction in viscosity. When the formulation is left standing without shear force, the viscosity is recovered over time.
• the term“gel” means a jelly-like materia!. Gels can be in a liquid, a semi-liquid, or a semi-solid state.
• the gel can be a liquid gel where the amount of gelling agent or geiiing effect is lower, such that the gel structure or connections are weaker or looser so that when placed in a tube and tilted from a vertical position to a horizontal position, the gel more readily flows and adapts to the horizontal position.
• temperatures can influence the release and bioabsorption of drugs therefrom.
• liquid gel refers, inter alia, to a formulation where the gel is loose or fluid or such that when subjected to gravity, it will pour or become liquid
• “foam” has its ordinary meaning to one of skill in the art, e.g., it may refer to an object or substance formed by trapping gas pockets within a solid or liquid.
• the gas pockets may comprise a gas, e.g., oxygen, nitrogen, or a mixture of gases, e.g , helium and xeon, or afmospheric air or alkanes gases.
• the gas pockets within the foam may be connected to each other, e.g., closed-cell foams or discrete, e.g., open-cel! foams.
• foamabie compositions refers to any composition that has the ability to form a foam in some embodiments
• foamabie compositions comprise a carrier with or without a liquefied or compressed gas propellant, that forms a foam when the carrier is brought in contact with the propellant or by mechanical means, such as an air pump in some embodiments, a foamabie composition is packaged in an aerosol container together with a pressurized propellant.
• the foamabie composition is separate from the propellant such as in a bag in can system in some embodiments, a valve on the aerosol container is actuated to release the foamable composition to form a foam
• a formulation disclosed herein comprises water.
• a formulation disclosed herein is water free.
• the terms“waterless” or“water-free,” refer to compositions that contains no free or unassociated or absorbed water in some embodiments, a waterless or water-free composition comprises 0.0% added water by weight. Such a composition may contain trapped, bound, associated or otherwise unfree water, e.g., within its higher order crystal structure.
• the terms“essentially waterless” or“essentially water-free” refer to compositions that comprise less than 0.05% of water by weight. In some embodiments, an essentially water-free composition comprises 0.04%, 0.03%, 0.02%, or 0.01 % water by weight.
• substantially waterless compositions that comprise less than 0.5% of water by weight.
• a substantially water-free composition comprises 0.4%, 0.3%, 0.2%, or 0.1 % water by weight.
• “low water” refers to a composition that contains about or less than 1% of water by weight.
• a composition with low water comprises 0.9%, 0.8%, 0.7%, 0.6% or 0.5% of water by weight.
• single phase means that, after preparation the liquid components of the composition or carrier are fully miscible, and the solid components, if any, are either dissolved or homogeneously suspended in the composition so that only one phase is visible.
• foamable composition“single phase” means that, after addition of propellant to the
• composition or carrier the liquid components of the foamable composition or carrier are fully miscible, and the solid components, if any, are either dissolved or homogeneously suspended in the composition so that only one phase is visible.
• a composition has a single phase before addition of propellant in some embodiments, a composition has a single phase after addition of propellant.
• the term“substantially a single phase” it is meant that the composition or carrier, after preparation, is primarily or essentially a single phase as explained above, but can also have present a small amount of material which is capable of forming a separate phase amounting to less than about 5% by weight of the composition or carrier after the addition of propeiiant, e.g., less than about 3% by weight, or less than about 1% by weight of the composition
• the composition or carrier, after addition of propellant is primarily or essentially a single phase as explained above, but can also have present a small amount of material which is capable of forming a separate phase amounting to less than about 5% by weight of the composition or carrier after the addition of propellant, e.g., less than about 3% by weight, or less than about 1 % by weight of the composition.
• a composition may be substantially a single phase before addition of propellant and a substantially single phase after addition of propeiiant. In some embodiments a composition may be substantially a single phase before addition of propeiiant and a single phase after addition of propeiiant. in some embodiments a composition may be a single phase before addition of propellant and substantially a single phase after addition propeiiant.
• the term“unstable” or“chemically unstable” as used herein, refers to a compound, e.g , an agent, which is oxidized, degraded, and/or reacts within a day, upon exposure to air, light, skin, water, any pharmaceutical excipient, or any active agent under ambient conditions.
• an unstable compound is partially [e.g , 5%, 10%, 50%, 75%) or fully degraded in less than 24 hours, e.g., less than 16 hours, less than 12 hours, less than 6 hours, less than 5 hours, less than 4 hours, less than 3 hours, less than 2 hours, or less than 1 hour, upon exposure to air, light, skin, water, or any pharmaceutical excipients under ambient conditions or any active agent.
• a physically unstable compound or composition changes its physical state in less than 24 hours, e.g., less than 16 hours, less than 12 hours, less than 6 hours, less than 5 hours, less than 4 hours, less than 3 hours, less than 2 hours, or less than 1 hour.
• “unstable active agent” or“chemically unstable active agent” as used herein refers to an active agent (e.g., minocycline HCl, or adapalene), or a part thereof which is oxidized, degraded, and/or reacts (“undergoes change”) within a day upon exposure to air, light, skin, water, or a pharmaceutical excipient under ambient conditions.
• an active agent e.g., minocycline HCl, or adapalene
• an unstable active agent or a part thereof undergoes change in less than 24 hours, e.g., less than 18 hours, less than 12 hours, less than 6 hours, less than 5 hours, less than 4 hours, less than 3 hours, less than 2 hours, or less than 1 hour, upon exposure to air, light, skin, water, or any pharmaceutical excipients under ambient conditions.
• the term“physically unstable active agent” as used herein refers to a substance or compound e.g., an active agent, or a part thereof which aggregates, clumps, sediments, separates out or otherwise changes its physical state under ambient conditions within a day. it can also refer to a composition comprising one or more active agents which within a day changes its physical state under ambient conditions.
• a physically unstable active agent changes its physical state in less than 24 hours, e.g., less than 16 hours, less than 12 hours, less than 8 hours, less than 5 hours, less than 4 hours, less than 3 hours, less than 2 hours, or less than 1.
• surfactant refers to compounds that on their own, can both reduce surface tension between two substances or phases, and also stabilize an emulsion of water and oil. Reduction of surface tension in foam technology changes a material’s ability to create small stable bubbles.
• surfactants include non-ionic, ionic, anionic, cationic, zwitterionic, amphoteric and amphiphilic surfactants.
• Surfactants may be derivatives of fatty alcohols or fatty acids, such as ethers or esters formed from such fatty alcohols or fatty acids with hydrophilic moieties, such as polyethylene giycoi (PEG).
• “Surfactant,”“emulsifier,” and“surface active agent,” as used herein, do not include compounds which do not function effectively on their own to reduce surface tension between two substances or phases and stabilize an emulsion of water and oil.
• a native (non-derivatized) fatty alcohol or fatty acid, as well as a wax generally does not reduce surface tension between two substances or phases or stabilize an emulsion of water and oil on its own, and therefore is not considered a surfactant in the context used herein.
• propoxylated lanolin oil derivatives are not themselves surfactants or emulsifiers.
• foam adjuvants in formulations disclosed herein comprise fatty acids and/or fatty alcohols.
• formulations disclosed herein comprise emollients
• emollient refers to a material or agent that, when placed in contact with the human skin, is able to soften, smoother!, reduce scaling and itching, reduce inflammation, improve skin barrier function, and/or act as a carrier for active agents.
• An emollient can comprise one or more oils.
• emollients include but are not limited to avocado oil, isopropyl myristate, mineral oil, capric triglycerides, capryllic triglyceride, isopropyl paimitate, isopropyl isostearate, diisopropyl adipate, diisopropyl dimerate, maleated soybean oil, octyl paimitate, cetyl lactate, cetyl ricinoleate, tocophery!
• co-surfactant refers to a molecule which on its own is not able to form and stabilize an oil-in-water emulsion, but when used in combination with a surfactant as defined herein, the co-surfactant can help a surfactant create an emulsion and can boost the stabilizing power or effect of the surfactant.
• co-surfactants include fatty alcohols, such as cetyl alcohol, or fatty acids, such as stearic acid. Cetyl alcohol is a waxy hydrophobic substance that can be emulsified with water in combination with a surfactant. Some substances can have more than one function and for example, fatty alcohols can in some formulations act as a co-solvent.
• a co-surfactant can itself be converted into a surfactant or soap by, for example, adding a base, such as, triethanolamine to a fatty acid like stearic acid.
• a base such as, triethanolamine
• viscosity- modifying agent in the context of the present disclosure is an agent which, when added to a hydrophobic oil, facilitates the creation of a hydrophobic breakable vehicle in the form of a breakable gel or breakable foam.
• the viscosity-modifying agent in relation to a foamabie composition, is also referred to as a“foamer complex," a“foam stabilizer” or a“foam adjuvant”, comprising, e.g., a fatty alcohol, a fatty acid and/or a wax.
• the foam adjuvant is a fatty alcohol and a wax or a fatty acid and a wax. in some embodiments it is a wax.
• the foam adjuvant or viscosity modifying agent comprises at least one of a fatty alcohol, a wax or a fatty acid.
• the foam adjuvant or viscosity modifying agent is selected from a group consisting of a fatty alcohol, a wax and a fatty acid.
• the foam adjuvant is a fatty alcohol.
• the foam adjuvant is a fatty acid.
• the foam adjuvant is a wax.
• a wax has the properties of a foam adjuvant in some embodiments a fatty alcohol, and/or a fatty acid and/or a wax is an adjuvant.
• fatty alcohols, fatty acids and waxes that are compatible with tetracycline antibiotics, and in particular with a minocycline or a doxycyc!ine are compatible adjuvants.
• compatible adjuvants comprise fatty alcohols, fatty acids and waxes compatible with retinoids, and in particular with adapalene.
• a formulation disclosed herein may include one or a combination of waxes.
• a wax may have a melting point temperature of about 36 °C or higher.
• a wax may have a melting point temperature of about 40 °C or higher.
• a wax may have a melting point temperature of about 49 °C or higher.
• a wax may have a melting point temperature of about 81 °C or higher in some embodiments, a wax may have a melting point temperature of about 83 °C or higher. In some embodiments, a wax may have a melting point temperature of about 88 °C or higher in some embodiments, a wax may have a melting point temperature of about 61 °C or higher. In some embodiments, a wax may have a melting point temperature of about 65 °C or higher. In some embodiments, a wax may have a melting point temperature of about 50 °C or higher. In some
• a wax may have a melting point temperature of about 54 °C or higher. In some embodiments, a wax may have a melting point temperature of about 57 °C or higher. In some embodiments, a wax may have a melting point temperature of about 60 °C or higher in one or more embodiments, the formulations provided herein comprise a wax, wherein the wax within the formulation has a melting point of 68-69 °C. In one or more embodiments, the formulations provided herein comprise a wax, wherein the wax within the formulation has a melting point of 42-44 °C. in some embodiments, a wax may have a melting point temperature of about 83-88 °C.
• a wax may have a melting point temperature of about 61 -65 °C. in some embodiments, a wax may have a melting point temperature of about 50-54 °C. In some embodiments, a wax may have a melting point temperature of about 57- 60 °C.
• breakable refers to a property of a gel or foam wherein the gel or foam is stable upon dispensing from a container yet breaks and spreads easily upon application of shear or mechanical force, which can be mild, such as a simple mechanical rub
• water activity represents the hygroscopic nature of a substance, or the tendency of a substance to absorb water from its surroundings Microorganisms require water to grow and reproduce, and such water requirements are best defined in terms of water activity of the substrate.
• a“solvent,” as used herein, is not intended to characterize the solubilization capabilities of the solvent for any specific active agent or any other component of the composition or foamable composition. Rather, such information is provided to aid in the identification of materials suitable for use as a component of the composition or foamable composition described herein.
• hydrophobic gel composition or“hydrophobic foamable composition” or“hydrophobic foam composition” or“hydrophobic composition” as used herein refer to compositions that have a low solubility in water. In some embodiments, 100 to 1000 parts of water are needed to dissolve or render miscible 1 part of the composition. In some embodiments, 1 000 to 10,000 parts of water are needed to dissolve or render miscible 1 part of the composition. In some embodiments,
• more than 10,000 parts of water are needed to dissolve or render miscible 1 part of the composition.
• the term“essentially free of” an ingredient as used herein is intended to mean that the composition comprises less than about 0.05% by weight of the ingredient, unless specifically indicated otherwise
• the term“free of an ingredient used herein, is intended to mean that the composition does not comprise any amount of the ingredient, unless specifically indicated otherwise e.g. where the ingredient is present in a trapped, bound, associated or otherwise untree state.
• “surfactant-free” or“emulsifier-free” or“non-surfactant” refer to compositions which comprise no or negligible levels of surfactants, emulsitiers, or surface-active agents. Where a formulation includes insignificant or de minimis amounts of surfactants, emulsifiers, or surface-active agents it is considered to be essentially surfactant-free. As used herein,“essentially free” indicates less than about 0.05% by weight of a surfactant, e.g., a surfactant selected from the group consisting of non-ionic, ionic, anionic, cationic, zwitterionic, amphoteric and amphoiytic surfactants.
• a surfactant selected from the group consisting of non-ionic, ionic, anionic, cationic, zwitterionic, amphoteric and amphoiytic surfactants.
• substantially surfactant-free relates to a composition that contains a total of about or less than 0.5% by weight a surfactant, e.g., a surfactant selected from the group consisting of non-ionic, ionic, anionic, cationic, zwitterionic, amphoteric and amphoiytic surfactants.
• the composition comprises about or less than 0.2% by weight of a surfactant; about or less than 0.15% by weight; about or less than 0.1 % by weight; about or less than 0.05% by weight; or about or less than 0.01 % by weight.
• the term“preventing” refers to avoiding the onset of a disorder or condition from occurring in a subject that has not yet been diagnosed as having the disorder or condition, but who may be susceptible to it.
• the term“treatment” or“treating” reters to inhibiting, reversing, ameliorating, or reducing the disorder or condition, e.g., arresting its development; relieving the disorder or condition, e.g., causing regression of the disorder or condition or reversing the progression of the disorder or condition;
• slowing progression or relieving or reducing one or more symptoms of the disorder or condition.
• it can also mean preventing or helping to prevent the disorder or condition or one or more symptoms thereof.
• the term“clinical response to treatment”, (“clinical success” or“clinical taiiure”) in the context of acne conglobate, acne vulgaris or rosacea treatments is derived from efficacy evaluation endpoints.
• the term“lesion count” relates to the number of inflammatory lesions ⁇ e.g., papules and pustules) and/or the number of non-inflammatory lesions (e.g., open and closed comedones, also known as blackheads and whiteheads) present In a designated area of the body (e.g. , in case of face, on the forehead, left and right cheeks, nose and chin).
• primary efficacy endpoints are: (1 ) the proportion of patients achieving treatment success at Week 12 based on an investigator's Globa! Assessment (success is defined as a score of "clear” or “minimal” (e.g., IGA score of 0 or 1 respectively), and at least a two-category improvement from baseline), (2) the mean change from baseline in inflammatory lesion counts in each treatment group at Week 12, and (3) the mean change from baseline in non-inflammatory lesion counts in each treatment group at Week 12.
• Safety evaluations may include reported adverse events, local skin tolerability assessments, physical examinations, and vital signs.
• a clinical response or efficacy as used herein may refer, in some embodiments, to a quantifiable improvement in the severity of a disease, e.g., acne conglobate, acne vulgaris or rosacea, after the start of treatment, e.g., 4 weeks, 8 weeks, or 12 weeks after, compared to the baseline before treatment, or wherein according to any of the aforementioned endpoints a statistically significant reduction or improvement is demonstrated as compared to placebo in some embodiments, treatment efficacy is assessed by the absolute change in inflammatory lesion count after the start of treatment, e.g., 4 weeks, 8 wee ks, or 12 weeks after, compared to the baseline before treatment in some embodiments, treatment efficacy is assessed by a 2 -grade decrease on the Investigator Global Assessment (IGA) scale after the start of treatment and a score of 0 or 1 on the IGA scale after the start of treatment, e.g., 4 weeks, 8 weeks, or 12 weeks after, compared to the baseline before treatment in some embodiment
• treatment efficacy is assessed by a 2-grade decrease on the investigator Global Assessment (IGA) scale after the start of treatment, e.g., 4 weeks, 8 weeks, or 12 weeks after, compared to the baseline before treatment. In some embodiments, treatment efficacy is assessed by a score of 0 or 1 on the IGA scale after the start of treatment, e.g., 4 weeks, 8 weeks, or 12 weeks after, compared to the baseline before treatment. In some embodiments, treatment efficacy is assessed by the absolute change in inflammatory lesion count with treatment compared to placebo.
• IGA investigator Global Assessment
• treatment efficacy is assessed by the absolute change in non-inflammatory lesion count with treatment compared to placebo in some embodiments, treatment efficacy is assessed by a 2- grade decrease on the IGA scale with treatment compared to placebo. In some embodiments, treatment efficacy is assessed by a score of 0 or 1 on fhe IGA scale with treatment compared to placebo. In some embodiments, treatment efficacy is assessed by a 2-grade decrease on the IGA scale with treatment compared to placebo and a score of 0 or 1 on the IGA scale with treatment compared to placebo.
• administering is superior to vehicle (i.e.
• treatment with a combination product achieves a statistically superior result. For example, greater than 25-45% of patients receiving combination treatment may achieve IGA treatment success, e.g., about 35.9%, as compared to 10-20%, e.g., about 15.7%, of patients in the vehicle treatment group. In some embodiments, numerical superiority may be observed for efficacy endpoints for fhese comparisons at Week 12.
• the combination product is superior numerically to vehicle for the endpoint of absolute reduction in non-inflammatory lesion counts at Week 12.
• a mean lesion count reduction of about 25- 30, e.g., about - 25.9 (-53.83%) for the combination treatment group may be superior when compared to a reduction of about 15-25, e.g., about -24.1 ( -48.09%) for the vehicle treatment group.
• the combination product may be superior to each of (1 ) 3% minocycline alone foam and (2) 0.3% adapalene alone foam.
• a method of treating acne comprising topically administering a foamable composition at least once daily for at least 12 weeks to a target area on the patient having acne, wherein said
• the foamable composition comprises a hydrogenated castor oil, one or more foam adjuvants and or one or more waxes, e.g., lacking an active agent such as minocycline and/or adapalene.
• the composition lacks or has few Tmh crystals in some embodiments, the composition comprises wherein the composition comprises, consists of, or consists essentially of:
• the reduction in non-inflammatory lesion count from baseline after treatment with the composition free of bofh minocycline and adapalene is superior to a reduction with the composition free of adapalene, after eight weeks or less than eight weeks of treatment in some embodiments, the reduction in non inflammatory lesion count from baseline after treatment with a composition without minocycline is superior to treatment the composition free of both minocycline and adapalene, after eight weeks or less than eight weeks of treatment.
• treatment with the composition free of minocycline and adapalene results in more than 45% reduction in non-inflammatory lesions after twelve weeks of treatment.
• “regular basis” it is meant a repeated or repeatable interval of time which can be, by way of illustration, a part of a day, daily, once daily, twice daily, alternative daily, alternate daily, twice weekly, trice weekly, weekly, fortnightly, monthly or some other repeated or repeatable interval for an appropriafe period of time wherein a dose is to be applied.
• the repeated applications can be determined according to the needs of the subject and the disease or disorder in some embodiments, as few as three repeat doses is required.
• between 3 and 14 doses, between 14 and 28 doses, between 28 and 50 doses, between 50 and 75 doses, or between 75 and 100 doses are needed in some embodiments, where prolonged treatment or a long period of maintenance dosing is needed, at least one hundred, at least two hundred, or at least three hundred repeat doses are needed.
• By“daily dose” is intended that the dose is administered during each 24 hour period while allowing for the subject to miss a dose from time to time, and still having a treatment effect.
• the term“adverse events” describes any unfavorable or unintended sign, symptom, or disease that appears or worsens in a subject after the subject has commenced using the formulation. Examples of what can be considered an adverse event (AE) include any of the following: A new illness, an exacerbation of a sign or symptom of an underlying condition or of a concomitant illness unrelated to treatment, a sign or symptom as an effect of the study drug or comparator drug.
• the common term for such problems is“side effects,” and used by patients and physicians.
• An“important medical event” may not be immediately life-threatening or result in death or hospitalization but may be considered serious when, based upon appropriate medical judgment, may jeopardize the subject or require medical or surgical intervention to prevent one of the outcomes listed above.
• Examples of such medical events include allergic bronchospasm requiring intensive treatment in an emergency room or at home; blood dyscrasias or convulsions that do not result in inpatient hospitalization; or development of drug dependency or drug abuse.
• treatment - emergent adverse events e.g., upper respiratory tract infection and/or dry skin
• a combination product disclosed herein e.g., comprising minocycline and adapalene
• a combination product disclosed herein is well tolerated.
• the combination product may be assessed as having “none” or“mild” for burning/stinging, itching, dryness, scaling, erythema, and/or hyperpigmentation in a treated subject.
• the term“clinical failure,” as used herein, is defined as insufficient improvement or deterioration (i.e., an increase or no change in the number of lesions)
• crystal fingerprint is meant the type and distribution of crystal structures in a given formulation (whether a therapeutic composition with a therapeutic agent, or a carrier without a therapeutic agent).
• the crystal fingerprint may be described using one or more parameters known to one skilled in the art. Exemplary parameters include number and type of crystals in a given area when viewed in a light microscope, cross-sectional diameter, cross- sectional area, shape, melting temperature, enthalpy, flow point temperature, certain bands from X-ray crystallography, X-ray diffraction pattern, Raman spectroscopy, space group, and/or certain points of inflection or shift seen from DSC, and/or FTIR (Fourier Transform Infrared Spectroscopy) parameters.
• FTIR parameters may include wavenumber, band intensity, and band sharpness.
• FTIR analysis may be used to identify and characterize functional groups and changes in the interactions (i.e., hydrogen bonds) that occur during molecular self-assembly (i.e., crystallization, polymerization), molecular disassembly (i.e., melting) or compounds’ decomposition.
• Hydrogenated castor oii is mainly composed of 12-hydroxyl stearic acid molecules (i.e., trihydroxystearin), capable of molecular self-assembly through hydrogen bonding developed by the hydroxyl groups of different 12-hydroxyl stearic acid molecules.
• FTIR may measure the vibration of O and H molecules and serves as an indicator of hydrogen bond strength in some embodiments, a waveband observed in FTIR between 3000-3400 cm 1 indicates hydrogen bonding stretching vibration in a composition.
• light is shone at crystals and stronger H-bonds are indicated by a red shift to a lower frequency of waveband. This may be quantified by measuring the absorption of an FTIR waveband, e.g., by comparing wavelengths and/or calculating the area under the curve from the FTIR waveband absorption measurement. A larger area indicates stronger H-bonds A higher intensity band or a shift to a lower frequency may also indicate stronger H-bonds.
• multiple FTIR wavebands may be considered.
• a lower wavenumber, a higher intensity band, and/or a band of lower frequency e.g., a band between about 3350-3305 cm 1 ⁇ may be observed for a composition prepared with a holding process than for a composition prepared without a holding process, indicating stronger H-bonds.
• oils e.g., coconut oil, soybean oil, mineral oil, and/or cyclomethicone
• HCO e.g.
• HCO 1.2% HCO reveals the presence of hydrogen bonds (e.g., a waveband at the 3350 3305 crrr interval) when HCO is present.
• the frequency of the bands within the composition is indicated by the wavenumber, as measured by FTIR.
• the composition prepared by a holding step has lower frequency, as measured by FTIR, than that of a composition prepared without a holding step.
• the composition prepared by a holding step has lower frequency, as measured by FTIR, than that of a composition prepared by a continuous heating-cooling process.
• the composition having Tmh crystals has lower frequency, as measured by FTIR, than that of a composition lacking Tmh crystals or a composition having a smaller percentage by area of Tmh crystals as compared to the percentage of spherulite or plate crystals in the composition.
• the absorbance of the hydrogen bond vibrational bands in the composition is indicated by the wavenumber of the composition, as measured by FTIR.
• the composition prepared by a holding step has multiple wavebands as measured by FTIR, where at least one band absorbs at a lower wavenumber as measured by FTIR, as compared to a composition prepared without a holding step. In one or more embodiments this band is above 3300cm- 1 , e.g., when measured at 25°C or 50°C. in some
• this band is about 3000cm 1 . In some embodiments this band is about SOGO-SBOGcnr 1 in some embodiments this band is about 3300cnr 1 .
• the composition prepared by a holding step has a first band which absorbs at a lower wavenumber and a second band which absorbs at the same wavenumber, as measured by FTIR, as compared to a composition prepared without a holding step. In one or more embodiments the second band is below about 3000- 3600crrr 1 , e.g., below 3300cnr 1 . in some embodiments the second band is about 3200cm 1 .
• the composition prepared by a holding step has a first band which absorbs at lower wavenumber and a second band which absorbs at the same wavenumber, as measured by FTIR, as compared to a composition prepared by a continuous heating-cooling process.
• the composition has a first band which absorbs at lower wavenumber and a second band which absorbs at the same wavenumber, as measured by FTIR, as that of a composition lacking Tmh crystals or a composition having a smaller percentage by area of Tmh crystals as compared to the percentage of spherulite or plate crystals in the composition.
• the composition has a first band having a wavenumber of about 3301 -3312cm 1 when measured at 25°C, as measured by FTIR. In one or more embodiments, the composition has a band having a wavenumber of about 3320-3324cnr 1 when measured at 50°C, as measured by FTIR.
• the intensity of a band within the composition is indicated by the area under the band’s peak, as measured by FTIR.
• the intensity of the band in a composition prepared by a holding step is higher, as measured by FTIR, than those of a composition prepared without a hold step.
• the band is band 1
• the band is band 2 and in some embodiments the band is band 1 and 2.
• the intensity of the bands in a composition prepared by a holding step is higher, as measured by FTIR, than those of a composition prepared without a hold step.
• the intensity of these bands in a composition prepared by a holding step is higher, as measured by FTIR than that of a composition prepared by a continuous heating-cooling process. In one or more embodiments, the intensity of these bands in a composition prepared by a holding step is higher, as measured by FTIR than that of a lacking Tmh crystal or a composition having a smaller percentage by area of Tmh crystals as compared to the percentage of spheruiite or plate crystals in the composition.
• a composition prepared by a holding step has more hydrogen bonds between crystals, as measured by FTIR, than that of a composition prepared without a holding step. In one or more embodiments, a composition prepared by a holding step has more hydrogen bonds between crystals, as measured by FTIR, than that of a composition prepared by a continuous heating cooling process. In one or more embodiments, the composition has more hydrogen bonds between crystals, as measured by FTIR, than that of a composition lacking Tmh crystals or a composition having a smaller percentage by area of Tmh crystals as compared to the percentage of spheruiite or plate crystals in the composition.
• a change in intensity, as measured by small x-ray scattering indicates a change in crystal structure.
• a higher intensity, as measured by small x-ray scattering indicates crystals of higher order and /or crystals that are more closely packed.
• the composition prepared by a holding step shows higher intensity, as measured by small x-ray scattering, compared to a composition prepared without a holding step in one or more embodiments, the composition prepared by a holding step shows higher intensity, as measured by small x-ray scattering, compared to a composition prepared by a continuous heating-cooling process.
• the composition prepared by a holding step has crystals of high order in one or more embodiments, the composition prepared by a holding step has crystals that are closely packed. In one or more embodiments, the composition prepared by a holding step has crystals of higher order, as measured by small x-ray scattering, compared to crystals of a composition prepared by a continuous heating- cooling process. In one or more embodiments, the composition prepared by a holding step has crystals that are more closely packed, as measured by small x-ray scattering, compared to crystals of a composition prepared by a continuous heating- cooling process.
• a change in wide angle x-ray scattering pattern indicates a change in crystal polymorph.
• a composition prepared by a holding step shows no change in a wide angle x-ray scattering pattern as compared to a composition prepared by a continuous heating- cooling process.
• a composition prepared by a holding step has no change in crystal polymorph as compared to a composition prepared by a continuous heating-cooling process.
• the composition prepared by a holding step shows a change in a wide angle x-ray scattering pattern as compared to a composition prepared by a continuous heating-cooling process.
• a composition prepared by a holding step has a change in crystal polymorph as compared to a composition prepared by a continuous heating -cooling process.
• a crystal fingerprint is characterized by evaluating the average cross-sectional diameter in the longest dimension of one or more crystals in a formulation, e.g., to identify Tmh crystals in the formulation, or to identify plate and/or spherulite crystals in the formulation.
• a crystal fingerprint is characterized by evaluating the average cross-sectional area of one or more crystals in a formulation, e.g., to identify Tmh crystals in the formulation, or to identify plafe and/or spherulite crystals in the formulation.
• a crystal fingerprint is characterized by the percentage of Tmh crystals as compared to the percentage of spherulite or plate crystals in the composition.
• a crystal fingerprint is characterized by the melting temperature of the crystals in the composition in some embodiments, a crystal fingerprint is characterized by the percentage and/or distribution of different types of crystals in the composition.
• a crystal fingerprint is characterized by the X-ray powder diffraction pattern of the crystals in the composition.
• a crystal fingerprint is
• a composition prepared using a holding step may exhibit a crystal finger print with stronger hydrogen bonds than seen in a composition prepared without a hold step (e.g., it may exhibit a shift to lower frequency wave bands and/or higher intensity wave bands, as measured by FT1R)
• spherulites describes spheroidal crystal structures composed of acicular or fibrous crystals grouped around a centra! point that have an average area of about 20-30 pm 2 e.g., 23-25 pm 2 .
• the terms“plates,”“platelets,” or“plate-like structures” describe crystal units in which the structure is larger in a iwo-dimensionai plane as compared to a one- dimensional plane and has an average area of about 10-20 pm 2 e.g., 12-19 pm 2 .
• spherulites and plates, or a higher percentage of spherulites and plates are prepared in a continuous heating-cooling process than when using a hold step.
• the average area of a plate prepared in a holding process e.g., about 14-20 pm 2 is larger than that prepared in a continuous heating-cooling process e.g., about 10-14 pm 2 .
• nonuniform crystals and crystals with“non- uniform structures” describe crystals that have a nonuniform crystal structure, i.e., do not have a defined crystal pattern, and have higher melting temperatures.
• Nonuniform crystals include those that cannot be classified as spherulites or plates in some embodiments, the nonuniform crystals disclosed herein are tangled fibers. In some embodiments, tangled fibers exhibit a larger widest cross-sectional area and lack the regularity of the cross-sectional area observed in a spherulite or plate crystal.
• Tmh crystal describes crystals having a phase transition temperature T M 4 of about 86-80 e C, as measured by DSC, and are formed during a mixing and cooling process employing a hold step. Tmh crystals are observed as having a nonuniform structure.
• the TM4 of a Tmh crystal may shift upwards when adding active agents such as adapaiene and/or minocycline to a formulation in some embodiments, the Tmh crystals have stronger interactions between unit cells, e.g., the molecular forces (e.g., Van der Waa!s, hydrogen bonds etc.) participating in the formation of the crystal lattice are stronger in one or more embodiments the stronger interaction results from an increased number of such interactions or bonds.
• the Tmh crystals disclosed herein are structures with more Van Der Waals bonds.
• the Tmh crystals disclosed herein are structures with more hydrogen bonds.
• the Tmh crystals have stronger
• the Tmh crystals have stronger intra-molecuiar interactions.
• the crystal structure discloses a higher intensity when measures by x-ray crystallography.
• a formulation comprising Tmh crystals exhibits a DSC pattern comprising a melting temperature above 68°C, e.g., a melting temperature of about 68-73 g C, e.g., about 68-72 ? C, e.g., about 68-89 e C.
• a higher percentage and/or density of Tmh crystals are prepared when using a holding process.
• Tmh crystals provide a formulation comprising aTwn as measured by DSC that is about 3 S C or about 4 g C, or about 5 e G, or about 6 g C higher than that of a formulation prepared in a continuous heating-cooling process.
• a formulation comprising Tmh crystals has an SRS (raman) spectra in the range of about 1400-1500 cm-1 , with a peak at about 1446 cm-1 and having one or two shoulders at about 1465 cm-1 and/or at about 1425 cm-1.
• the differences observed between the crystals prepared using a continuous cooling process and those of the holding process described herein, e.g., those observed in a placebo formulation and/or a formulation comprising an active such as minocycline and/or adapelen include: Continuous process Holding process
• similar properties are expected in placebo formulations and those having an API, e.g., minocycline, e.g., minocycline hydrochloride, when prepared using a holding step.
• an API e.g., minocycline, e.g., minocycline hydrochloride
• “shakability” refers to the degree to which the user is able to feel or hear the presence of the foamabie composition when the filled pressurized canister is shaken. Shaking is done with mild to normal force without vigorous or excessive force. When the user cannot sense the motion of the contents during shaking the foamabie composition may be considered to be non-shakable. When the user can moderately sense the motion of the contents during the shaking, the foamabie composition is considered moderately shakabie. When the contents are f!owab!e during shaking, the product is considered shakabie.
• the composition and/or foamabie composition comprises crystals with a crystal fingerprint (including numbers, sizes, types and distribution etc.) that have not been described previously in the literature.
• the unique crystals have a higher order and or a nonuniform structure in one or more embodiments the presence of these unique crystals and/or said crystal fingerprint may alter the properties of the composition, and or foamabie composition e.g., by improving one or more characteristics including, usability, melting temperature, the ability to facilitate sebum liquification, fluidity, shakability, stability and storability.
• the crystals in the composition and/or foamabie composition helps reduce or eliminate a need for refrigeration or cool storage.
• the crystals and/or crystal fingerprint in the compositions and/or foamabie composifions can improve penetration, delivery and/or distribution into skin, mucosa or wall of a body cavity of one or more active pharmaceutical agents (e.g., MCH and ADR).
• the crystals increase the softening, breakdown, and/or dissolution of sebum. In one or more embodiments each of these improvements is achieved without compromising, impacting on, or reducing the chemical stability of the unstable active ingredients in the improved formulations
• the Tmh crystals in the formulations disclosed herein exhibit a fingerprint comprising Tmh crystals distributed throughout the formulation. In some embodiments the Tmh crystals are distributed
• the Tmh crystal forms appear to duster within the composition, e.g., as determined by observing a sample of a formulation under a light microscope to observe groupings of increased crystal density at locations throughout the sample, as compared to other locations in the sample or as compared to a sample from a formulation prepared without a hold step in some embodiments, these clusters are themselves homogeneously distributed throughout the formulation (e.g., as determined by observing a sample of a formulation under a light microscope to observe clusters of crystal density dispersed evenly throughout the sample).
• These Tmh crystals and/or the crystal fingerprints described herein can be obtained from the compositions and /or foamable compositions and/or methods described herein and as described more particularly below.
• Gel or foam compositions comprising, e.g., tetracycline antibiotic are described in U.S. Patent Application Publication Nos. 2014/0121 188 and
• hydrophobic gel or toamable composition comprising hydrogenated castor oil, wherein the
• a hydrophobic gel or foamable composition comprising a tetracycline antibiotic and hydrogenated castor oil, wherein the hydrogenated castor oil is present in an amount effective to form a stable foamable formulation.
• a hydrophobic gel or foamable composition comprising a tetracycline antibiotic and/or a retinoid, and hydrogenated castor oil, wherein the hydrogenated castor oil is present in an amount effective to form a stable foamab!e formulation.
• foamabie composition are for use in treating a skin disorder, e.g., acne conglobate, acne vulgaris or rosacea, in a human subject suffering therefrom.
• treatment methods using the foamabie are for use in treating a skin disorder, e.g., acne conglobate, acne vulgaris or rosacea, in a human subject suffering therefrom.
• compositions described herein comprise topically administering the composition to the human subject in a sufficient amount and for a sufficient time to achieve efficacy, e.g., decrease the number of inflammatory or non-inflammatory lesions or achieve IGA treatment success.
• hydrogenated castor oil is a saturated vegetable oil wax which may allow hydrophobic and hydrophilic components of the foamabie compositions or hydrophobic gels described herein to form a homogenous or uniform composition.
• Foamabie compositions comprising hydrogenated castor oil and produced by the methods described herein may provide for surprisingly improved stability, serving as a suitable carrier for active agents that may be easily degraded, e.g., a tetracycline antibiotic such as minocycline HCI and/or a retinoid such as adapalene.
• active agents e.g., a tetracycline antibiotic such as minocycline HCI and/or a retinoid such as adapalene.
• the methods and compositions described herein may produce a foamabie composition that has superior shakability and microcrystal structures.
• foamabie composition comprising hydrogenated castor oil, wherein the hydrogenated castor oil is present in an amount effective to form a stable foamabie formulation.
• the foamabie composition comprises about 1 % to about 3% hydrogenated castor oil. in some embodiments, the foamabie composition comprises about 1 % to about 2% hydrogenated castor oil. In some embodiments, the foamabie composition comprises about 1% to about 1 .5% hydrogenated castor oil. In some embodiments, the foamabie composition comprises about 1.1% to about 1.3% hydrogenated castor oil. In some embodiments, the foamabie composition comprises about 2%
• the foamabie composition comprises about 1.2% hydrogenated castor oil. In some embodiments, the foamabie composition comprises about 1 .9% to about 2.1 % hydrogenated castor oil.
• a cooling hold step as described herein with a formulation comprising hydrogenated castor oil may surprisingly prevent a reduction in Tm when adding hydrogenated castor oil to, e.g., a foamable formulation (compare, e.g., the drop in T reported in Example 2 when preparing formulations without a hold step).
• the carrier has a therapeutic effect.
• the carrier comprises one or more therapeutic agents in one or more embodiments the therapeutic agent is pharmaceutical active agent. In one or more embodiments it is present in a therapeutically effective amount for topical application to skin, mucosa or body cavity surface as would be appreciated by a physician skilled in such topical application.
• the therapeutic agent is a cosmetic or cosmeceutica! active agent. In one or more embodiments it is present in a therapeutically effective amount for topical application to skin, mucosa or body cavity surface as would be appreciated by a physician skilled in such topical application.
• the term“cosmeceutical agent” refers to a cosmetic agent that has one or more medicinal, therapeutic, and/or drug-like benefits.
• Non limiting examples include alpha hydroxy acids (AHAs), beta hydroxy acids (BHAs) and polyhydroxy acids (PHAs), vitamins such as vitamin A, vitamin B, vitamin B3, vitamin C, vitamin D, vitamin D3, vitamin E, vitamin derivatives, lipoic acid, salicylic acid, keratolytic agents, peeling agents, depigmenting (or bleaching) agents such as hydroquinone and kojic acid, botanical and marine extracts, UV filters, UV absorbers, lactic acid, retinol, retinoid and nicotinamide.
• AHAs alpha hydroxy acids
• BHAs beta hydroxy acids
• PHAs polyhydroxy acids
• vitamins such as vitamin A, vitamin B, vitamin B3, vitamin C, vitamin D, vitamin D3, vitamin E, vitamin derivatives, lipoic acid, salicylic acid, keratolytic agents, peeling agents,
• a cosmeceutical agent may be a pharmaceutical agent that is used at low doses to provide one or more benefits to skin and mucosa.
• a cosmeceutical agent can manipulate and/or modulate the biological function of the skin, e.g., improve appearance of the skin, such as skin tone, texture, clarity and/or wrinkles by delivering nutrients essential for healthy skin.
• the active agent comprises an antibacterial agent in certain embodiments, the antibacterial active agent is a tetracycline antibiotic.
• the tetracycline antibiotic is oxytetracycline, demeclocyc!ine, doxycydine, iymecycline, meclocyc!ine, methacycline, minocycline, roiitetracyciine, chlorotetracydine, tigecycline, or a mixture of two or more thereof.
• the tetracycline is minocycline or a salt thereof.
• the tetracycline is minocycline hydrochloride
• a formulation disclosed herein comprises minocycline, e.g., about 1 .5-3%, e.g., about 1 .5 % or about 3%.
• the minocycline is present as minocycline hydrochloride.
• the amount of minocycline hydrochloride in a formulation is adjusted to correspond to a total amount of minocycline of about 1 .5-3%.
• about 1 .29-3.58% of minocycline hydrochloride may be used to provide about 1 .50-3.00% of minocycline.
• the tetracycline is doxycyc!ine or a salt thereof in one or more embodiments, the tetracycline is doxycycline hyc!ate. in one or more embodiments, the tetracycline is doxycycline monohydrate. In one or more embodiments, the tetracycline antibiotic is present in a free base form, a hydrate form, a salt form, or a complex form. In one or more embodiments, the tetracycline is soluble or is partially soluble In the composition. In one or more embodiments, a part of the tetracycline is suspended in the composition. In one or more embodiments, properties or uses discovered for doxycycline or minocycline compositions can be applicable to other tetracycline antibiotic compositions.
• a composition provided herein comprises one or more active agents selected from, but not limited to, one or more of lysine, an active herbal extract, an acaricides, an age spot and keratose removing agent, an allergen, an alpha hydroxyl acid, an analgesic agent, an antiacne agent, an antiallergic agent, an antiaging agent, an antibacterial agent, an antibiotic, an antiburn agent, an anticancer agent, an antidandruff agent, an antidepressant, an antidermatitis agent, an antiedemic anent, an antifungal agent, an antihistamine, an antihelminth agent, an antihyperkeratolyte agent, an anti-infective agent, an antiinflammatory agent, an antiirritant, an antilipemic agent, an antimicrobial agent, an antimycotic agent, an antioxidant, an antiparasitic agent, an antiproliferative agent, an antipruritic agent, an antipsoriatic agent,
• a fungicide a hair growth regulator, a haptene, a hormone, a hydroxy acid, an immunosuppressant, an immunoregulating agent, an immunomoduiator, an insecticide, an insect repellent, a keratolytic agent, a lactam, a local anesthetic agent, a lubricating agent, a masking agent, a metals, a metal oxide, a mitocide, a neuropeptide, a non-steroidal anti-inflammatory agent, an oxidizing agent, a pediculicide, a peptide, a protein, a photodynamic therapy agent, a radical scavenger, a refatting agent, a retinoid, a sanative, a scabicide, a self-tanning agent, a skin protective agent, a skin whitening agent, a steroid, a steroid hormone, a vasoconstrictor, a vasodilator, a vitamin
• a composition provided herein comprises a tetracycline antibiotic and at least one additional active agent, for example, a terfracycline antibiotic and a retinoid, a tetracycline antibiotic and a steroid, or a tetracycline antibiotic and a retinoid and a steroid in one or more embodiments the retinoid is adapalene or tazarotene.
• the composition, and/or foamable composition can be a placebo (i.e., a vehicle or a carrier) composition.
• the composition, and/or foamable composition can be substantially free of an active agent.
• the composition, and/or foamable composition is essentially free of active agent in some embodiments, the composition, and/or foamable composition can be free of active agent.
• the composition, and/or foamable composition is suitable for use in the manufacture of a medicament.
• the methods of preparing the compositions described herein surprisingly improve the properties of a placebo composition, e.g., stability, shakability, f!owabi!ity etc.
• a placebo composition prepared by a holding process improves the properties of the composition, e.g., restoration of the enthalpy in the placebo to match that seen in a formulation with active agents.
• the composition includes at least two active agents, in a therapeutically effective concentration.
• the composition includes at least three active agents, in a therapeutically effective concentration.
• the composition includes at least four active agents, in a therapeutically effective concentration.
• the composition includes at least five active agents, in a therapeutically effective concentration.
• a combination of any two or more of an antibacterial, an anti-inflammatory, an antifungal, an antiviral agent and an immunomoduiating agent is contemplated.
• composition comprising a combination of an antibiotic and at least one additional active agent selected from the group consisting of a vasoconstrictor, an a2 adrenergic agonist, a tyrosine kinase inhibitor, a VEGF inhibitor, a JAK inhibitor, a dicarboxylic acid, a serine protease inhibitor, and an aldosterone receptor inhibitor.
• composition comprising a combination of a tetracycline antibiotic and at least one additional active agent selected irom the group consisting of brimonidine, pazopanib, tofacitinib, azeiaic acid, aminocaproic acid, and spironolactone.
• compositions comprising a combination of a minocycline and at least one additional active agent selected from the group consisting of brimonidine, pazopanib, tofacitinib, azeiaic acid, aminocaproic acid, and spironoiactone.
• a composition comprising a combination of a doxycydine and at least one additional active agent selected from the group consisting of brimonidine, pazopanib, tofacitinib, azelaic acid, aminocaproic acid, and spironolactone.
• composition in which the composition further comprises at least one additional active agent selected from the group consisting of an antibiotic agent, an anti-inflammatory agent, a steroidal anti- inflammatory agent, an immunosuppressive agent, an immunomodulator, an immunoregulating agent, a hormonal agent, an androgen, an estrogen, a
• prostaglandin an antiandrogen agent, a testosterone inhibitor, a dihydrotestosterone inhibitor, antibacterial agent, an antifungal agent, an antiviral agent, an antiparasitic agent, antimicrobial, a retinoid, vitamin A, a vitamin A derivative, vitamin B, a vitamin B derivative, vitamin C, a vitamin C derivative, vitamin D, a vitamin D derivative, vitamin E, a vitamin E derivative, vitamin F, a vitamin F derivative, vitamin K, a vitamin K derivative, a wound healing agent, a disinfectant, an anesthetic, an antiallergic agent, a keratolytic agent, urea, a urea derivative, an alpha hydroxyl acid, lactic acid, glycolic acid, a beta-hydroxy acid, a protein, a peptide, a neuropeptide, an allergen, an immunogenic substance, a haptene, an oxidizing agent, an antioxidant, a dicarboxylic acid, azelaic acid, sebacic acid,
• a derivative of an active agent it is intended to provide derivatives that are known and/or are used for and/or contemplated for treatment of skin, or mucosa, or a body cavity surface or wall.
• the addition of at least one additional active agent is optional.
• a specific active agent is used herein, it can be substituted by another form of the same active agent.
• minocycline hydrochloride can be substituted by another form of minocycline
• doxycycline hyclate can be substituted by another form of doxycycline.
• the term“form” can include, for example, salts, hydrates, crystals, polymorphs, enantiomers, isomers, ions, complexes, and the like in one or more embodiments, the active agent can be in the form of a sait, a hydrate, a crystai, one or more polymorphs, one or more
• a tetracycline antibiotic is the sole active ingredient present in the composition.
• a minocycline is the sole active ingredient present in the composition in one or more embodiments
• a doxycycline is the sole active ingredient present in the composition in one or more embodiments, minocycline and doxycycline are used in combination.
• the effect of these quaternary ammonium derivatives of anesthetic drugs is associated with TRPA1 , TRPM8, P2X(2/3) or TRPVI channels and receptors in one or more embodiments they bind to receptors on the side of the channels which is internal.
• a combination of any two or more of tetracycline antibiotics, a retinoid, azelaic acid and benzoyl peroxide is
• a combination of a tetracycline antibiotic, and a JAK inhibitor e.g., baricitinib or tofacitinib is contemplated.
• a combination of any two or more of benzoyl peroxide, antibiotics, tetracycline antibiotic, retinoids, antiseborrheic medications, anti-androgen medications, hormonal treatments, lactic acid, urea, petrolatum, emollients, salicylic acid, alpha hydroxy acid, azelaic acid, nicotinamide, and a keratoiytic agent is contemplated.
• the tetracycline is in combination with of one or more of an antihistamine, a corticosteroid, doxepin, or adapaiene.
• the concentration of the additional active agent is in a range between about 0.1 % to about 15% by weight (e.g., about 0.1 % to about 14% by weight, about 0.1 % to about 12% by weight about 0.1 % to about 10% by weight about 0.1 % to about 8% by weight, or about 0.1 % to about 5% by weight, or about 0 1 % to about 3% by weight, or about 0.1 % to about 2% by weight, or about 0.1 % to about 1 % by weight, or about 0.1 % to about 0.75% by weight, or about 0.1 % to about 0.5% by weight, or about 0.1 % to about 0.25% by weight, or about 0.25% to about 10% by weight, or about 0.5% to about 10% by weight, or about 1 % to about 10% by weight, or about 2% to about 10% by weight, or about 4% to about 10% by weight, or about 6% to about 10% by weight, or about 7% to about 10% by weight, or about 2% to about 10% by weight, or about
• the concentration of the additional active agent is about or at least about 0.05% by weight, is about or is at least about 0.1 % by weight, is about or at least about 0.2% by weight, is about or at least about 0.3% by weight, is about or at least about 0.4% by weight, is about or at least about 0.5% by weight, is about or at least about 0.8% by weight, is about or at least about 0 8% by weight or at least about 1 % by weight, is about or at least about 1 ,5% by weight, is about or is at least about 2% by weight, is about or at least about 2.5% by weight, is about or at least about 3% by weight, is about or at least about 3.5% by weight, is about or at least about 4% by weight, is about or at least about 4.5% by weight, is about or at least about 5% by weight or at least about 5.5 % by weight, agent is about or at least about 5.5% by weight, is about or is at least about 6% by weight, is about or at least about 6.5% by weight, is about or at least about or at
• Any unstable topical therapeutic or active agent e.g. a tetracycline antibiotic, may be used with the formulations disclosed herein Similarly, any stable topical therapeutic or active agent may be used on their own or in combination with any unstable active agent in the formulations disclosed herein in some
• any tetracycline antibiotic known to one of skilled in the art can be used with the formulations disclosed herein.
• a tetracycline antibiotic include, for example, but not limited to tetracycline, oxytetracyciine, demedocydine, doxycycline, !ymecycline, mec!ocyc!ine, methacycline, minocycline, rolitetracycline, chlorotetracyc!ine, and tigecyciine.
• the tetracycline is a minocycline or
• the tetracycline is minocycline.
• the minocycline is minocycline
• MCH hydrochloride
• MCH is a yellow crystalline powder that is sparingly soluble in water, slightly soluble in alcohol, and/or practically insoluble in chloroform and in ether. MCH may be quickly degraded when dissolved in water. Without being bound by any theory, degradation of small amounts of dissolved MCH can hasten the dissolution of more MCH which in turn degrade, and which may drive a cycle of rapid degradation.
• Minocycline and MCH are known to be highly sensitive to moisture, air and light and undergo rapid degradation. The presence of even small amounts of water can cause degradation. Compatible excipients have become incompatible in the presence of water. Addition of antioxidants did not alter this result. Therefore, storage of formulations in airtight/lighttight sealed containers or tubes or foamable formulations in airtight/lighttight sealed containers under pressure with propellant can contribute to preserving stability, subject to selection of compatible canisters and accessories. Likewise, production and/or filing under vacuum in an oxygen free environment and purging with nitrogen can help
• foamable compositions comprising hydrogenated castor oil and a tetracycline antibiotic, e.g., minocycline, when applied topically, provide therapeutic benefits for skin disorders, e.g., acne conglobate, acne vulgaris or rosacea.
• the ease of use, with once daily dosing, as well as its broad spectrum of activity, early onset, the low level of adverse events and the rapid reduction in the number of lesions make it an attractive choice and a potentially valuable medication for the treatment of acute bacterial skin infections.
• Examples of bacterial infections that can be effectively treated by topical tetracycline antibiotics include, but not limited to, cellulitis, acute lymphangitis, lymphadenitis, erysipelas, cutaneous abscesses, necrotizing subcutaneous infections, staphylococcal scalded skin syndrome, folliculitis, furuncles, hidradenitis suppurativa, carbuncles, paronychial infections, erythrasma, disorders of hair follicles and sebaceous glands, acne, impetigo, rosacea, perioral dermatitis, hypertrichosis (hirsutism), alopecia, including male pattern baldness, alopecia greata, alopecia universalis and alopecia totaiis, pseudofoiiicuiitis barbae, and keratinous cyst.
• rosacea involves papules and pustules, which can be treated with an antibiotic agent, as well as erythema, telangiectasia, and redness, which partially respond to treatment with an antibiotic agent.
• acne vulgaris involves papules, pustules, open or dosed comedones, and nodules, which can be treated with an antibiotic agent.
• the tetracycline antibiotic has some hydrophobic/ lipophilic properties.
• the Log of the distribution constant of the tetracycline antibiotic at pH 7.0 is equal to or less than about 0.2.
• tetracycline antibiotic forms suitable for use according to the methods and compositions of the present disclosure include, but are not limited to, a free base form, a hydrate form, a salt form, a chelate complex form or a coordination complex form.
• the tetracycline antibiotic does not comprise a hydroxyl group at carbons 5, 6, and 7.
• the tetracycline antibiotic comprises or is selected from the group consisting of a minocycline and a doxycyciine.
• the tetracycline antibiotic is a minocycline.
• the concentration of the tetracycline antibiotic for topical application e.g.
• minocycline is in a range between about 0.1 % to about 12% by weight (e.g., about 0.1 % to about 1 1 % by weight, about 0.1 % to about 10% by weight, about 0.1 % to about 9% by weight, about 0.1 % to about 8% by weight, about 0.1% to about 7% by weight, about 0.1 % to about 6% by weight, about 0.1 % to about 5% by weight, about 0.1 % to about 4% by weight about 0.1 % to about 3% by weight, about 0.1 % to about 2% by weight, about 0.1 % to about 1 % by weight, about 0.1% to about 0.75% by weight, about 0.1 % to about 0.5% by weight, about 0.1 % to about 0.25% by weight, about 0.25% to about 10% by weight, about 0.5% to about 10% by weight, about 0.5% to about 5% by weight, about 0 5% to about 4% by weight, about 0.5% to about 3% by weight, about 1 % to about 10% by weight
• the concentration of the tetracycline antibiotic e.g , minocycline is about or at least about 0.05% by weight, is about or at least about 0.1 % by weight, is about or at least about 0.5% by weight, is about or at least about 1 % by weight, is about or at least about 1 5% by weight, is about or at least about 2% by weight, is about or at least about 2 5% by weight, is about or at least about 3% by weight, or is about or at least about 3 5% by weight, is about or at least about 4% by weight, is about or at least about 4.5% by weight, is about or at least about 5% by weight, is about or at least about 5.5% by weight, is about or at least about 6% by weight, is about or at least about 6.5% by weight or is about or at least about 7% by weight, is about or at least about 7.5% by weight, is about or at least about 8% by weight, is about or at least about 8 5% by weight, is about or at least about 9% by weight,
• reference to by weight means by weight of the topical composition and with reference to foamabie compositions without the addition of propellant.
• the therapeutic agent e.g., a tetracycline antibiotic and/or a retinoid
• the therapeutic agent is micronized.
• the therapeutic agent is not micronized.
• the active agent is micronized so that the diameter of 90% of the particles (d (0.9)), is less than about 30 microns, or less than about 20 microns, or less than about 10 microns.
• the average size of the micronized particles is about 30 microns to about 0.5 microns or about 25 microns to about 1 microns or about 20 microns to about 2 microns or about 15 microns to about 3 microns or about 12 microns to about 3.5 microns or about 10 micron
• the initial dose of the tetracycline antibiotic is about 18%, about 17.5%, about 16.5%, about 15.5%, about 14.5%, about 13.5%, about 12.5%, about 1 1 .5%, about 10.5%, about 9.5%, about 8.5%, about 7.5%, about 6.5%, about 5.5%, about 4.5%, about 3.5%, about 2.5%, about 1 .5%, about 17%, about 16%, about 15%, about 14%, about 13%, about 12%, about 1 1 %, about 10%, about 9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about 2%, about 1 %, about 0.75%, about 0.5%, about 0.25%, or about 0.2% by weight of the composition.
• the maintenance dose of the tetracycline antibiotic is about 7.5%, about 6.5%, about 5.5%, about 4.5%, about 3.5%, about 2.5%, about 1 .5%, about 7%, about 6%, about 5%, about 4%, about 3%, about 2%, about 1 %, about 0.5%, about 1 .9%, about 1 .8%, about 1 .7%, about 1.6%, about 1 .55, about 1 .4%, about 1 .3%, about 1 .2%, about 1 .1 %, about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.4%, about 0.35, about 0.25%, about 0.2%, about 0.15%, or about 0.1 % by weight of the composition.
• foamable compositions comprising a tetracycline antibiotic, such as a minocycline, for use in treatment of acne conglobate, acne vulgaris or rosacea, and/or acne conglobate, acne vulgaris or rosacea related symptoms, and/or a tetracycline antibiotic responsive rosacea related disorder, and/or a tetracycline antibiotic responsive acne vulgaris related disorder, and/or a tetracycline antibiotic responsive skin disorder, and/or skin disorder caused by a bacteria, and/or a tetracycline antibiotic responsive disorder, and/or a sebaceous gland disorder in one or more embodiments the tetracycline is used for the treatment of rosacea.
• a tetracycline antibiotic such as a minocycline
• the tetracycline antibiotic is used for the treatment of impetigo in one or more embodiments the tetracycline antibiotic is used for the treatment of acne. In one or more embodiments the tetracycline antibiotic is used for the treatment of acne vulgaris in one or more embodiments the tetracycline antibiotic is used for the treatment of non-infiammatory lesions. In one or more embodiments the tetracycline antibiotic is used for the treatment of inflammatory lesions in one or more embodiments the tetracycline antibiotic is used for the treatment of comodones. In one or more embodiments the tetracycline antibiotic acts to reduce oxidative stress and/or inflammation in skin pathologies in one or more embodiments the tetracycline antibiotic is effective where the condition is accompanied by apoptotic cell death.
• foamab!e compositions comprising a minocycline or a doxycydine for use in treating acne conglobate, acne vulgaris or rosacea, and/or acne conglobate, acne vulgaris or rosacea related symptoms, and/or a tetracycline antibiotic responsive rosacea related disorder, and/or a tetracycline antibiotic responsive acne vulgaris related disorder, and/or a tetracycline antibiotic responsive skin disorder, and/or skin disorder caused by a bacteria, and/or a tetracycline antibiotic responsive disorder, and/or a sebaceous gland disorder.
• minocycline or doxycydine is used for the treatment of acne. In one or more embodiments minocycline or doxycydine is used for the treatment of acne congiobata or acne vulgaris in one or more embodiments the tetracycline antibiotic is used for the treatment of inflammatory and/or non-infiammatory acne. In one or more embodiments the minocycline or doxycydine is used for the treatment of comodones. In one or more embodiments minocycline or doxycydine is used for the treatment of rosacea.
• compositions, and/or foamable compositions comprising a wax, such as hydrogenated castor oil (e.g., about 0.1 % to about 2%, or about 0.2% to about 1 .4%, or about 0.3 to about 1 .2% hydrogenated castor oil), a tetracycline antibiotic, and/or at least one additional active agent.
• active agents include but are not limited to retinoids, benzoyl peroxide, salicylic acid, alpha hydroxy acid, resorcinol, dicarboxyiic acids e.g., azelaic acid, immunomodulators, e.g. JAK inhibitors (e.g., Toficitinib), and sulfur.
• retinoids may be comedo!ytic, resolve the precursor microcomedone lesion, and provide anti-inflammatory effects.
• an active agent in a composition, and/or foamable compositions disclosed herein comprises a retinoid.
• the composition, and/or foamable compositions comprises about 0.1 % to about 10% by weight of a retinoid, (e.g., about 0.1 % to about 9%, about 0 1 % to about 8%, about 0 1 % to about 7%, about 0.1 % to about 6%, about 0.1 % to about 5%, about 0.1 % to about 4%, about 0.1 % to about 3%, about 0.1 % to about 2%, about 0.1 % to about 1 %, about 0.1 % to about 0.5%, about 0.1 % to about 0.4 %, or about 0.1 % to about 0.3% by weight of the composition in some embodiments, the composition, and/or foamable composition, comprises about 0.1 %, about 0.15%, about 0.2%, about 0.25%, about 0.3%, about 0.35%, about 0.4%, about 0.45%, or about 0.5% by weight of a retinoid (e.g., adapa!ene).
• a retinoid
• the concentration of the retinoid (e.g. adapaiene). In some embodiments the concentration is about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.08%, about 0.08%, about 0.1 1 %, about 0.13%, about 0.15%, about 0.17%, about 0 19%, about 0.275%, about 0.325%, about 0.375%, about 0.425%, about 0.475%, about 0.55%, about 0.6%, about 0.65%, or about 0.7% or can be a range between any two figures listed in this paragraph, such as, 0.05% to about 0.7%.
• the retinoid comprises adapaiene (also referred to as“ADR”).
• reference to by weight means by weight of the topical composition and with reference to foamable compositions without the addition of propellant.
• the active agent e.g., tetracycline antibiotic
• the active agent is encapsulated.
• the active agent is encapsulated in particles, microparticles, nanoparticles, microcapsules, microspheres, nanocapsuies, nanospheres, liposomes, niosomes, polymer matrices, silica-gels, graphite, nanocrystals, or microsponges.
• such particles can have various functions, such as (1 ) protection of the drug from degradation; (2) modification of the drug release rate from the composition; (3) control of skin penetration profile; and (4) mitigation of adverse effects, due to the controlled release of the active agent from the encapsulation particles.
• the tetracycline antibiotic is encapsulated.
• the tetracycline active ingredient is associated with solid, porous microcarriers, each having a hydrophobic surface.
• the solid, porous microcarriers comprise a material selected from the group consisting of hydrophobic surface-modified silicon dioxide, porous polystyrene, porous polyamide, porous hydrophobic cellulose, and porous poiytetrafluoroethylene.
• the microcarrier possesses a porous structure for retaining the active ingredient, a hydrophobic surface, and is chemically non-reactive with the active ingredient.
• the hydrophobic encapsu!ant comprises a material selected from the group consisting of mineral oil, petrolatum jelly, synthetic waxes, natural waxes, and silicone oils.
• the average encapsulant particle size is less than 95 microns, less than 75 microns, less than 50 microns, less than 25 microns, less than 22 microns, or less than 15 microns.
• the average encapsulated particle size of the tetracycline antibiotic is about 5.5 to about 10.5 microns, about 6 microns to about 10.5 microns, about 6.5 microns to about 10 microns, about 7 microns to about 9.5 microns, or about 7.5 microns to about 9 microns.
• compositions, and/or foamabie compositions comprising one or more emollients.
• the composition comprises a wax, such as hydrogenated castor oil (e.g., about 0.1 % to about 2%, about 0.2% to about 1 .4%, or about 0.3 to about 1 .2% hydrogenated castor oil), and at least one or more emollients.
• hydrogenated castor oil e.g., about 0.1 % to about 2%, about 0.2% to about 1 .4%, or about 0.3 to about 1 .2% hydrogenated castor oil
• emollients may reduce scaling and itching, reduce inflammation, improve skin barrier function, and act as a carrier for active agents.
• the emollient comprises one or more vegetable oils.
• the emollient comprises one or more animal or fish oils.
• the emollient comprises one or more mineral oils in some embodiments the emollient comprises combinations of two or more of vegetable, animal, fish and mineral oil.
• emollients include but are not limited to an avocado oil, isopropyl myristate, a mineral oil, a MGT oil, capric triglyceride, caprylic triglyceride, isopropyl palmitate, isopropyl isostearate, diisopropyl adipate, diisopropyl dimerate, a maieated soybean oil, octyl palmitate, cetyl lactate, cetyl ricinoleate, tocopheryl acetate, acetylated lanolin alcohols, cetyl acetate, phenyl trimethicone, glyceryl oleate, tocopheryl iinoleate, wheat germ glycerides, arachidyl propionate, myristy!
• lactate decyl oleate, ricinoleate, isopropyl lanolate, pentaerythrityl tetrastearate, neopentyiglycol dicapryiate/dicaprate, isononyi isononanoate, isotridecyi isononanoate, myristyl myristate, triisocetyl citrate, octyl dodecanoi, unsaturated or polyunsaturated oils, an olive oil, a corn oil, a soybean oil, a canola oil, a cottonseed oil, a coconut oil, a sesame oil, a sunflower oil, a safflower oil, a borage seed oil, a syzigium aromaticum oil, a bempseed oil, a herring oil, a cod-liver oil, a salmon oil, a flaxseed oil, a wheat germ oil, an evening primrose oil, an essential oil,
• the foamable composition comprises an emollient, wherein the emollient is coconut oil. In some embodiments, the foamable composition comprises an emollient, wherein the emollient is light mineral oil. In some embodiments, the foamable composition comprises an emollient, wherein the emollient is isopropyl myristate. in some embodiments, the foamable composition comprises an emollient, wherein the emollient is a coconut oil. In some
• the foamable composition comprises an emollient, wherein the emollient is soybean oil. In some embodiments, the foamable composition comprises an emollient, wherein the emollient is cyciomethicone. In some embodiments, the foamable composition comprises at least one or more of an emollient, selected from cyciomethicone, coconut oil, light mineral oil, isopropyl myristate and soybean oil. In some embodiments an emollient is selected having similar or closely equivalent properties thereto. [00208] In one or more embodiments the emollient is or comprises a hydrophobic oil.
• composition and/or a foamable
• composition comprises about 55% to about 95% of at least one emollient by weight in some embodiments, the composition, and/or a foamable composition comprises about 58% to about 93%, about 60% to about 91 %, about 62% to about 89%, about 64% to about 87%, about 66% to about 85%, about 68% to about 84%, about 70% to about 83%, about 72% to about 82% of at least one emollient by weight of the composition in some embodiments, the composition and/or a foamable composition comprises about 40% to about 60% by weight of soybean oil. In some embodiments, the composition, and/or a foamable composition comprises about 45% to about 55% by weight of soybean oil.
• the composition and/or a foamable composition comprises about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51 %, about 52%, about 53%, about 54%, or about 55%, by weight of soybean oil.
• the composition, and/or a foamable composition comprises about 20% to about 25% by weight of coconut oil.
• the composition, and/or a foamable composition comprises about 22% to about 25%, or about 23% to about 24% by weight of coconut oil.
• the composition, and/or a foamable composition comprises about 20%, about 21 %, about 22%, about 23%, about 24%, or about 25% by weight of coconut oil.
• the composition, and/or the foamable composition comprises about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51 %, about 52%, about 53%, about 54%, or about 55%, by weight of soybean oil.
• the composition, and/or a foamable composition comprises about 20% to about 25% by weight of coconut oil.
• composition comprises about 23.6% by weight of coconut oil.
• composition, and/or the foamable composition comprises about 1 % to about 8% by weight of mineral oil (e.g., light mineral oil) in some embodiments, the
• composition, and/or the foamable composition comprises about 2% to about 8%, about 3% to about 7.5%, about 3.5% to about 7%, or about 4% to about 7%, by weight of mineral oil.
• the composition and/or the foamable composition comprises about 1 %, about 1 .2%, about 1.4%, about 1 .6%, about 1 .8%, about 2%, about 2.2%, about 2.4%, about 2.6%, about 2.8%, about 3%, about 3.2%, about 3.4%, about 3.6%, about 3.8%, about 4%, about 4.2%, about 4.4%, about 4.6%, about 4.8%, about 5%, about 5.2%, about 5.4%, about 5.6%, about 5.8%, about 6%, about 6.2%, about 6.4%, about 6.6%, or about 6.8% by weight of mineral oil.
• the foamable composition, and/or the foamable composition comprises about 3.3% to about 6.6% by weight of mineral oil. In some embodiments, the composition, and/or the foamable composition comprises about 3% to about 7% by weight of cyciomethicone. In some embodiments, the
• composition, and/or the foamable composition comprises about 3 5% to about 6 5%, or about 3.8% to about 6.2%, or about 4% to about 6%, by weight of
• the composition, and/or the foamable composition comprises about 3.4%, about 3.6%, about 3.8%, about 4%, about 4.2%, about 4.4%, about 4.6%, about 4.8%, about 5%, about 5.2%, about 5.4%, about 5.6%, about 5.8%, about 6%, about 6.2%, about 6.4%, about 6.6%, about 6.8%, or about 7% by weight of cyciomethicone.
• compositions, and/or foamable compositions comprising one or more foam adjuvants.
• a composition comprises a wax, such as hydrogenated castor oil (e.g., about 0.1 % to about 2%, about 0.2% to about 1 .4%, or about 0.3 to about 1 .2% hydrogenated castor oil), and at least one or more foam adjuvants in combination with one or more active agents it is postulated, without being bound by any theory, that the use of foam adjuvants contributes to stability, viscosity, and smoothness of the foamable composition, allowing active agents to be delivered efficaciously to a desired target.
• Foam adjuvants that may be used in compositions, and/or foamable compositions are known to persons with skill in the art, and include but are not limited to fatty acids, and fatty alcohols.
• a foam adjuvant can include a fatty alcohol.
• fatty alcohols Long chain saturated and mono-unsaturated fatty alcohols, e.g., steary! alcohol, erucyl alcohol, arachidyl alcohol and behenyl alcohol (docosanol) have been reported to possess antiviral, anti-infective, anti-proliferative and anti-inflammatory properties (see, U.S. Pat. No. 4,874,794).
• Longer chain fatty alcohols e.g , tetracosanol, hexacosanol, heptacosanol, octacosanol, triacontanol, etc., are also known for their metabolism modifying properties, and tissue energizing properties.
• the fatty alcohol comprises or is selected from the group consisting of lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, cetostearyl alcohol, arachidyl alcohol, behenyl alcohol, tetracosanol, hexacosanol, octacosanol, triacontanol, and tetratriacontanol or mixtures of any two or more thereof.
• a foam adjuvant can include a fatty acid.
• the fatty acid comprises or is selected from the group consisting of dodecanoic acid, tetradecanoic acid, hexadecanoic acid,
• heptadecanoic acid heptadecanoic acid, octadecanoic acid, eicosanoic acid, docosanoic acid, tetracosanoic acid, hexacosanoic acid, heptacosanoic acid, octacosanoic acid, triacontanoic acid, dotriacontanoic acid, tritriacontanoic acid, tetratriacontanoic acid, and pentatriacontanoic acid or mixtures of any two or more thereof.
• the carbon chain of the fatty alcohol or the fatty acid is substituted with a hydroxyl group.
• the composition is hydrophobic in one or more embodiments, the composition comprises one or more hydrophobic oils and waxes in one or more embodiments, the composition comprises one or more fatty alcohols. In one or more embodiments, the composition comprises one or more waxes. In one or more embodiments, the composition comprises one or more fatty acids.
• the foam adjuvant is about 0.1 % to about 20% by weight of the composition, and/or foamable compositions.
• the compositions, and/or foamable compositions comprise about 0.2% to about 15%, about 0.3% to about 14%, about 0.4% to about 13%, about 0.5% to about 12% of a foam adjuvant (e.g., stearyl alcohol, myristyi alcohol, cetyl alcohol, cetostearyl alcohol, and/or behenyi alcohol).
• a foam adjuvant e.g., stearyl alcohol, myristyi alcohol, cetyl alcohol, cetostearyl alcohol, and/or behenyi alcohol.
• the compositions and/or foamable compositions comprise about 0.6% to about 1 1 %, about 0.7% to about 10%, or about 0.8% to about 9%, of a foam adjuvant.
• compositions and/or foamable compositions comprise about 0.8% to about 8%, about 0 8% to about 7%, about 0.7% to about 7%, about 0.5% to about 7%, about 0.6% to about 6%, about 0.7% to about 5%, about 0.8% to about 3%, about 1 % to about 2%, or about 1 .2% to about 1 .8% by weight of a foam adjuvant.
• the compositions, and/or foamable compositions comprise about 0.1 %, about 0.25%, about 0.5%, about 0.75%, about 1 %, about 1 .1 %, about 1 .2%, about 1.4%, about 1 .5%, about 1 .6%, about 1 .8%, about 2%, about 2.2%, about 2.4%, about 2.5%, about 2.6%, about 2.8%, about 3%, about 3.2%, about 3.4%, about 3.5%, about 3.6%, about 3.8%, about 4%, about 4.2%, about 4.4%, about 4.6%, about 4.8%, about 5%, about 5.5% by weight, about 6%, about 6.5%, about 7%, about 7.5%, about 8%, or about 8.5% by weight individually of a foam adjuvant ).
• the foam adjuvant is stearic acid. In one or more embodiments, the foam adjuvant is docosanoi. In one or more
• the foam adjuvant is stearyi alcohol.
• the compositions, and/or foa able compositions comprise about 1% to about 2% by weight of stearyi alcohol.
• the compositions, and/or foamable compositions comprise about 1 .2% to about 1.8% by weight of stearyi alcohol.
• the compositions and/or foamable compositions comprise about 1.5% by weight of stearyi alcohol.
• the foam adjuvant is cetosfearyl alcohol in some embodiments, the compositions and/or foamable compositions comprise about 2% to about 5% by weight of cetostearyl alcohol in some embodiments, the compositions and/or foamable compositions comprise about 3% to about 4% by weight of cetostearyl alcohol in some embodiments, the compositions and/or foamable compositions comprise about 3.5% by weight of cetostearyl alcohol. In one or more embodiments, the foam adjuvant is myristyl alcohol.
• compositions and/or foamable compositions comprise about 1.8% to about 3.3% by weight of myristyl alcohol in some embodiments, the compositions, and/or foamable compositions comprise about 2% to about 3% by weight of myristyl alcohol. In some embodiments, the compositions and/or foamable compositions comprise about 2.5% by weight of myristyl alcohol.
• the compositions, and/or foamable compositions comprise at least one or more of a wax.
• the wax can assist in foaming.
• waxes are lipophilic and soluble in hydrophobic solvents, and may provide a suitable carrier for active agents that are otherwise easily degraded when exposed to water or other pharmaceutical excipients.
• waxes may aid the compositions, and/or foamable compositions in forming crystals with nonuniform shapes, plates, or spherulites and may contribute substantially to the crystal fingerprint of such compositions.
• Waxes, or mixtures of waxes may also control the viscosity of the foamabie compositions, allowing them to flow or be shakable.
• a wax used in a composition disclosed herein has a melting temperature of about 36 °C or higher in some embodiments, a wax has a melting temperature of about 49 °C or higher, or about 81 °C or higher. In one or more embodiments the wax is solid at 36 e C or more. In one or more
• the wax is solid at 49 e C or more in one or more embodiments the wax is solid at 81 S C or more.
• the formulations provided herein comprise a wax, wherein within the formulation said wax has a melting point of 68-69 °C. In one or more embodiments, the formulations provided herein comprise a wax, wherein within the formulation said wax has a melting point of 42-44 °C.
• foamabie compositions comprise at least one or more of a wax selected from the group consisting of a plant wax, a white wax, an emulsifying wax, a carnauba wax, a cande!i!ia wax, a cerasine/ozokerite wax, a Japan wax, a castor wax, a microcrystalline wax, a montan wax, a peat wax, an ouricury wax, a sugarcane wax, a retamo wax, a jojoba oil, an animal wax (e.g.
• lanolin spermaceti wax, and wool fat
• beeswax a shellac wax
• a hydrogenated oil e.g., a hydrogenated castor oil, or a hydrogenated cotton seed oil
• petroleum derived wax e.g., a paraffin wax, polyethylene wax, and derivatives thereof.
• Waxes that remain solid at room or body temperature may be used in the formulations disclosed herein and may form microcrystals that are homogenously distributed within the foamabie formulations described herein.
• the type, number, and distribution of crystals within the formulation may change its rheological properties, ultimately having an effect on the stability and usability of the formulation in some embodiments, larger wax crystals may also be found distributed within the formulation.
• compositions and/or foamabie compositions comprising a wax, such as hydrogenated castor oil (e.g., about 1 .2% hydrogenated castor oil) further comprise a combination of two waxes, or sometimes three waxes, or sometimes four waxes, or sometimes five waxes, or six or more waxes.
• a wax such as hydrogenated castor oil (e.g., about 1 .2% hydrogenated castor oil)
• hydrogenated castor oil e.g., about 1 .2% hydrogenated castor oil
• compositions, and/or foamabie compositions comprise about 0.1 % to about 7% by weight of a wax.
• compositions, and/or foamable compositions comprise about 0.1 % to about 6%, about 0.1 % to about 5%, about 0.1 % to about 4% about 0 15% to about 3.7%, 0.2% to about 3.6% , about 0.3% to about 3 5%, about 0.4% to about 3.4%, about 0.5% to about 3.3%, about 0.6% to about 3.2%, about 0.7% to about 3.1 %, about 0 8% to about 3%, about 1 % to about 3%, about 0.8% to about 2.75%, 0.8% to about 2.5%, about 0.8% to about 2.25%, about 0.8% to about 2%, about 1 % to about 2%, about 1 .1 % to about 1 .9%, or about 1 .2% to about 1 .8% by weight of a wax.
• compositions, and/or foamable compositions comprise about 0.1 %, about 0.25%, about 0.5%, about 0.75%, about 1 %, about 1 .2%, about 1.4%, about 1 .5%, about 1 .6%, about 1 .8%, about 2%, about 2.2%, about 2.4%, about 2.6%, about 2.8%, about 3%, about 3.2%, about 3.4%, about 3.5%, about 3 6%, about 3.8%, about 4%, about 4.2%, about 4.4%, about 4.6%, about 4.8%, about 5%, about 5.5% or about 6% by weight individually of each wax (e.g.
• a foamable composition comprises about 0.1 % to about 3% by weight of a HCO. in one or more embodiments, foamable compositions comprise about 0.4% to about 2.2% by weight of HCO. In one or more embodiments, foamable compositions comprise about 0.6% to about 1 .8%, or about 0.8% to about 1 .6% by weight of HCO. In one or more embodiments, foamable compositions comprise about 1 % to about 1 .4% by weight of HCO. In one or more embodiments, foamable compositions comprise about 1 .2% by weight of HCO.
• foamable compositions comprise about 0.1 % to about 4% by weight of a white wax. In one or more embodiments, foamable compositions comprise about 1 % to about 3% by weight of a white wax. In one or more embodiments, foamable compositions comprise about 2% by weight of a white wax.
• the ratio of HCO to beeswax in the formulation is between about 1 :20 and about 20:1 , for example about 1 :20, about 1 :19, about 1 :18, about 1 :17, about 1 :16, about 1 :15, about 1 :14, about 1 :1 3, about 1 :12, about 1 :1 1 , about 1 :10, about 1 :9, about 1 :8, about 1 :7, about 1 :6, about 1 :5, about 1 :4, about 1 :3, about 1 :2, about 1 :1 , about 2:1 , about 3:1 , about 4:1 , about 5:1 , about 6:1 , about 7.1 , about 8:1 , about 9:1 , about 10:1 , about 1 1 :1 , about 12:1 , about 13:1 , about 14:1 , about 15:1 , about 16:1 , about 17:1 , about 18:1
• the ratio of HCO to beeswax in the formulation is between about 1 :12 and about 12:1 , for example between about 1 :10 and about 10:1 , about 1 :8 and about 8:1 , about 1 :6 and about 6:1 about 1 :4 and about 4:1 , about 3:10 and about 10:3, about 1 :2 and about 2:1 about 3:5 and about 5:3, or about 2:3 and about 3:2 In some embodiments the ratio is about 1 :1. In one or more embodiments, the ratio between HCO and beeswax in the formulation is between about 0.3:1 and about 1.7:1.
• the composition comprises about 0.1% w/w to about 0.4% w/w of fumed (modified) silica or silica dioxide. In one or more embodiments, the composition comprises about 0.125% w/w to about 0.35%, or about 0.15% to about 3% w/w of fumed (modified) silica or silica dioxide. In some embodiments, the composition is substantially free of fumed (modified) silica or silica dioxide. In some embodiments, the composition is essentially free of fumed
• the composition is free of fumed (modified) silica or silica dioxide.
• the foamable compositions described herein are packaged in an aerosol container and pressurized with a propellant in one or more embodiments, the foamable composition further comprises a propellant.
• a propellant Any compatible propellant can be used.
• the propellant is a gas at room temperature under normal pressure and which can be liquefied at increased pressure at room temperature.
• propellants include, without limitation, hydrocarbon propellants such as butane, propane, isobutane, dimethyl ether, fluorocarbons such as 1 ,1 ,1 ,2 tetrafluoroethane (Dymel 134a), and
• the foamable compositions described herein are pressurized with a hydrocarbon mixture comprising butane, propane, and isobutene. In some embodiments, the foamable compositions described herein are pressurized with a hydrocarbon mixture comprising AP-70 (a mixture of about 30% w/w butane, 20% w/w isobutane and 50% w/w propane) is used.
• AP-70 a mixture of about 30% w/w butane, 20% w/w isobutane and 50% w/w propane
• the foamabie compositions described herein are pressurized with a hydrocarbon mixture comprising AP-46 (about 16% w/w of propane, about 82% w/w of isobutane and about 2% w/w of propane) in some embodiments, the foamabie compositions described herein are pressurized with hydro fluorocarbon (HFC) propellants in one or more embodiments, the foamabie compositions described herein are pressurized with compressed gases (e.g., air, carbon dioxide, nitrous oxide, and nitrogen).
• HFC hydro fluorocarbon
• the propellant is a self-foaming propellant, i.e., a volatile liquid having a boiling point of less than the temperature of the target treatment site (such as the skin).
• the propellant is isopentane.
• any concentration of the propellant, which forms an acceptable foam, is useful in accordance with the present invention.
• the propellant makes up between about 1% to about 30% of the foamabie composition, or about 3% to 30%, about 3% to 25%, about 4% to about 20%, or about 5% to about 18% of the composition.
• the ingredients other than propellant are combined to 100% and the propellant is added thereafter so that the ratio of formulation to propellant can range from about 100:1 to about 100:30, about 100:3 to about 100:30, about 100:3 to about 100:25, about 100:4 to 100:20, or about 100:5 to about 100:18.
• the ratio of formu!afion to propellant is between about 100:20 and about 100:50.
• the formulations do not comprise chlorofiuorocarbons (CFGs).
• the propellant could be mixed with the formulation at between about 1 % to 3%, between about 2% to 4%, or between about 3% to 5% propellant (ratio of formulation to propellant of 100:1 to 100:3, 100:2 to 100:4, or 100:3 to 100:5 respectively) while keeping a further amount of propellant separate from the formulation.
• the propellant can also be used to expel the formulation using a bag- in-can system or a can-in-can system as will be appreciated by someone skilled in the art.
• part of the propellant system is in the formulation and part of it is kept separate from the formulation using a bag-in-can or can-in-can system.
• a pump or other mechanical means is used to provide expulsion force.
• the composition is free of one or more of a petrolatum, surface active agents, protic solvents, polar aprotic solvents, isopropyl myristate, polyethylene gelling agents, polyethylene homopo!ymers, polyethylene copolymers, selenium derivatives and silicone thickening agents.
• the foamable composition is essentially free of one or more of petrolatum, surface active agents, protic solvents, certain polar aprotic solvents, isopropyl myristate, polyethylene gelling agents, polyethylene homopolymers, polyethylene copolymers, selenium derivatives and silicone thickening agents.
• the foamable composition is substantially free of one or more of petrolatum, surface active agents, protic solvents, certain polar aprotic solvents, isopropyl myristate, polyethylene gelling agents, polyethylene homopolymers, polyethylene copolymers, selenium derivatives and silicone thickening agents.
• the composition comprises less than about 0.4% by weight of each one or more of petrolatum, surface active agents, protic solvents, certain polar aprotic solvents, isopropyl myristate, polyethylene gelling agents, polyethylene homopolymers, polyethylene copolymers, selenium derivatives and silicone thickening agents.
• the composition comprises less than about 0 4% by weight in total of one or more of petrolatum, surface active agents, protic solvents, certain polar aprotic solvents, isopropyl myristate, polyethylene gelling agents, polyethylene homopoiymers, polyethylene copolymers, selenium derivatives and silicone thickening agents.
• the composition comprises less than about 0.2% by weight of each one or more of petrolatum, surface active agents, protic solvents, certain polar aprotic solvents, isopropyl myristate, polyethylene gelling agents, polyethylene homopoiymers, polyethylene copolymers, selenium derivatives and silicone thickening agents in some embodiments, the composition comprises less than about 0.2% by weight in total of one or more of petrolatum, surface active agents, protic solvents, polar aprotic solvents, isopropyl myristate, polyethylene gelling agents, polyethylene homopolymers, polyethylene copolymers, selenium derivatives and silicone thickening agents.
• the composition comprises less than about 0.1 % by weight of each one or more of petrolatum, surface active agents, protic solvents, certain polar aprotlc solvents, isopropyl myristate, polyethylene gelling agents, polyethylene homopolymers, polyethylene copolymers, selenium derivatives and silicone thickening agents. In some embodiments, the composition comprises less than about 0.1 % by weight in total of one or more of petrolatum, surface active agents, protic solvents, certain polar aprotlc solvents, isopropyl myristate, polyethylene gelling agents, polyethylene homopolymers, polyethylene copolymers, selenium derivatives and silicone thickening agents.
• the composition, and/or foamble composition is substantially alcohol-free, i.e., substantially free of short chain alcohols having up to 5 carbon atoms in their carbon chain skeleton.
• the composition comprises less than about 5% by weight final concenfration of shorf chain alcohols, for example, less than 2% by weight, or less than 1 % by weight in certain embodiments, the composition is free, or essentially free of ethanol, propanol, butanol and pentanol.
• the composition and/or foamab!e composition disclosed herein further comprises a surfactant.
• the surfactant is non-ionic.
• the surfactant is ionic.
• the surfactant is zwitterionic.
• the foa ab!e composition comprises less than about 10% of a surfactant, e.g., less than about 5%, less than about 3%, less than about 2%, less than about 1 %, or less than about 0.1% of a surfactant.
• the formulations disclosed herein are substantially surfactant-free.
• the formulations disclosed herein are essentially surfactant-free.
• the formulations disclosed herein are surfactant-free.
• a formulation disclosed herein lacks a non-ionic surfactant.
• non-ionic surfactants include: (i) polyoxyethylene sorbitan esters (poiysorbates), such as polysorbate 20, polysorbate 40, polysorbate 60 and polysorbate 80; (ii) sorbitan esters, such as sorbitan monolaurate and sorbitan monoo!eate; (iii) polyoxyethylene fatty acid esters, such as, PEG-8 stearate, PEG-20 stearate, PEG-40 stearate, PEG-100 stearate, PEG-150 distearate, PEG-8 laurate, PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-8 oleate, PEG-9 oleate, PEG-10 oleate, PEG-12 oieate, PEG-15 oleate and PEG-20 oieate; (poiysorbates), such as polysorbate 20, poly
• the composition can comprise of one or more of a petrolatum, surface active agents, protic solvents, polar aprotic solvents, isopropyl myristate, polyethylene gelling agents, polyethylene homopolymers, polyethylene copolymers, selenium derivatives and silicone thickening agents.
• the composition is free or essentially free of an active agent or an unstable active agent and comprises of one or more of a petrolatum, surface active agents, protic solvents, polar aprotic solvents, isopropyl myristate, polyethylene gelling agents, polyethylene homopolymers, polyethylene copolymers, selenium derivatives and silicone thickening agents.
• the composition comprises an unstable active agent and can also comprise of one or more of a petrolatum, surface active agents, protic solvents, polar aprotic solvents, isopropyl myristate, polyethylene gelling agents, polyethylene homopolymers, polyethylene copolymers, selenium derivatives and silicone thickening agents.
• a petrolatum surface active agents
• protic solvents polar aprotic solvents
• isopropyl myristate polyethylene gelling agents
• polyethylene homopolymers polyethylene copolymers
• selenium derivatives and silicone thickening agents.
• compositions disclosed herein comprise protic solvents, such as short chain alcohols, glycols and glycerin.
• protic solvents such as short chain alcohols, glycols and glycerin.
• the compositions disclosed herein are free, or essentially free, or substantially free of protic solvents.
• compositions disclosed herein comprise aprotic solvents in some embodiments, the compositions disclosed herein are free, or essentially free, or substantially free of aprotic solvents.
• PCI Publication No. W01 1 /G39637 indicates that certain polar aprotic solvents may be incompatible with tetracycline antibiotics in some embodiments, formulations disclosed herein are free, or essentially free, or substantially free of aprotic polar solvents, such as dimethyl sulfoxide (DMSO), dimethylformamide (DMF), acetonitrile, acetone, methyl ethyl ketone, 1 ,4-Dioxane and tetrahydrofuran (THF), N-methyipyrrolidone, pyridine, piperidine, dimethylformamide, N-methyl-2- pyrrolidone and 1 -mefhyl-2-pyrro!idinone) and azone (1 -dodecylazacycloheptan-2- one).
• DMSO dimethyl sulfoxide
• DMF dimethylformamide
• acetonitrile acetone
• compositions disclosed herein may comprise one or more silicone thickening agents, such as an elastomer in some embodiments.
• a thickening agent is used in place of soybean oil, e.g.,
• Silicone thickening agents may comprise one or more polysiloxane-derived components. Such poiysiioxanes are typically cross-linked, have rubber-like characteristics, and require solubilization in an oil, e.g., a silicone oil.
• An example of a silicone thickening agent is the ST- Eiastomer 10 (Dow Corning), which is a mixture of high molecular weight dimethicone crosspolymer (12%) in cyclopentasiloxane (cyclomethicone, silicone solvent).
• compositions and/or foamabie compositions comprise one or more silicone thickening agents.
• composition and/or the foamabie composition is
• compositions and/or the foamabie composition are substantially free of a silicone thickening agent.
• the composition and/or the foamabie composition is essentially free of a silicone thickening agent.
• the composition and/or the foamabie composition is free of a silicone thickening agent.
• the composition is free or substantially free of silicone thickening agents other than cyclomethicone.
• elastomers are provided, e.g., in high amounts, e.g., in the range of about 86% to about 96% by weight of the composition, for example, about or more than 86%, 88%, 90%, 92%, 94%, 95%, or 96%. in some embodiments, elastomers are provided in amounts in the range of about 30% to about 54% by weight of the composition, for example, about or more than 34%,
• the compositions and/or foamable compositions is substantially free of elastomers in one or more other specific embodiments, the compositions and/or foamable compositions is essentially free of elastomers in some embodiments, the compositions and/or foamabie compositions comprises less than about 30% silicones, less than about 25% silicones, less than about 20% silicones, less than about 15% silicones, less than about 10% silicones, less than about 7.5% silicones, less than about 5% silicones, less than about 2% silicones, less than about 1 % silicones, less than about 0.75% silicones, less than about 0.5% silicones, or less than about 0.25% silicones in some embodiments, the compositions and/or foamabie compositions comprises about 1 % to about 5% silicones, or about 0.5% to about 3% silicones.
• compositions and/or foamabie compositions does not comprise a silicone other than cyclomethicone. in some embodiments, In some embodiments, the compositions and/or foamabie compositions does not comprise one or more volatile silicones in some embodiments, volatile silicones are present at about 3% or less.
• semi-solid hydrophobic oils are a subsidiary component in the composition, for example being present at less than about 45%, at less than about 40%, at less than about 35%, at less than about 30%, at less than about 25%, less than about 20%, less than about 15%, less than about 10%, or less than about 5% by weight of the composition in one or more alternative embodiments, semi-solid oils are omitted.
• compositions and/or foamable compositions may comprise a polyol.
• the identification of a“polyol,” as used herein, is an organic substance that contains at least two hydroxyl groups in its molecular structure.
• the polyol is a diol (a compound that contains two hydroxyl groups in its molecular structure e.g. propylene glycol).
• the polyol is a triol (a compound that contains three hydroxyl groups in its molecular structure, such as glycerin).
• the polyol is a saccharide.
• exemplary saccharides include, but are not limited to, monosaccharides (e.g., ribose, glucose, fructose, and galactose), disaccharides (, such as sucrose, maltose, and/or lactose), oligosaccharides, and sugar alcohols (e.g. mannitol, sorbitol, xy!itoi, maititoi, !actito!).
• monosaccharides e.g., ribose, glucose, fructose, and galactose
• disaccharides such as sucrose, maltose, and/or lactose
• oligosaccharides such as sucrose, maltose, and/or lactose
• sugar alcohols e.g. mannitol, sorbitol, xy!itoi, maititoi, !actito!
• the composition is polyol free, i.e., free of polyols.
• the composition and/or the foamable composition is essentially free of polyols.
• the composition and/or foamable composition is substantially free or essentially free or free of a diol.
• the composition and/or foamable composition is substantially free or essentially free or free of a triol.
• the composition and/or foamable composition is substantially free or essentially free or free of a saccharide.
• the composition and/or foamable composition is substantially free or essentially free or free of a sugar alcohol.
• the composition and/or foamable composition comprises less than about 5%, less than about 2%, less than about 1%, or less than about 0 5% by weight of polyols. In some embodiments, the composition and/or foamable composition comprises about 1% to about 5%, or about 0.5% to about 3% by weight of polyols.
• a composition can include one or more additional components.
• additional components include but are not limited to anti-static agents, buffering agents, bulking agents, chelating agents, cleansers, colorants, conditioners, deodorants, diluents, dyes, emollients, fragrances, humectants, perfuming agents, permeation enhancers, pH-adjusting agents, preservatives, protectants, skin penetration enhancers, softeners, solubilizers, sunscreens, sun blocking agents, viscosity modifiers and vitamins.
• additional components include but are not limited to anti-static agents, buffering agents, bulking agents, chelating agents, cleansers, colorants, conditioners, deodorants, diluents, dyes, emollients, fragrances, humectants, perfuming agents, permeation enhancers, pH-adjusting agents, preservatives, protectants, skin penetration enhancers, softeners, solubilizers, sunscreens, sun blocking
• a composition and/or a foamabie composition comprising: an unstable active agent, such as a tetracycline antibiotic alone or in combination with one or more other active ingredients such as a retinoid; and a wax, such as a hydrogenated castor oil, wherein the wax is present in the composition in an amount effective to form a stable foamabie formulation in some embodiments the wax comprises a hydrogenated oil. In some embodiments the wax comprises hydrogenated castor oil.
• the tetracycline antibiotic is tetracycline, oxytetracycline, demeclocycline, doxycyciine hyclate, lymecycline, meclocycline, methacydine, minocycline hydrochloride, rolitetracycline, chlorotetracydine, or tigecydine.
• the tetracycline antibiotic is present in the composition at a concentration of about 0.5% to about 10% by weight; about 1 % to about 4% by weight; about 1.5% by weight; or about 3% by weight.
• the tetracycline antibiotic is a minocycline.
• the minocycline is minocycline hydrochloride.
• the minocycline hydrochloride is present in the composition at a concentration of about 1 .5% by weight; about 3.0% by weight, or between about 1 .5% and about 3% by weight.
• the additional active agent comprises a retinoid.
• the retinoid is adapalene or tazarotene.
• the retinoid is adapalene.
• the retinoid is present in the composition at a concentration of about 0.1 % to about 1 % by weight, about 0.1% to about 0.5% by weight; about 0.2% by weight, about 0.3% by weight, or about 0.4% by weight in one or more embodiments the retinoid is adapalene and the adapalene is present in the composition at a concentration of about 0.1 % to about 0.5% by weight, or between about 0.1% to about 0.3% by weight.
• the composition and/or foamabie composition comprises about 1-3%, or about 1 -2%, or about 1 .2%, hydrogenated castor oil. in some embodiments the composition and/or foamabie composition comprises about 1.2% hydrogenated castor oil.
• the composition and/or foamabie composition further comprises (a) about 60% to about 95% by weight of at least one emollient and (b) about 5% to about 25% by weight at least one foam adjuvant, or a combination thereof in one or more embodiments the composition comprises: a) about 40% to about 60% by weight of soybean oil; b) about 20% to about 25% by weight of coconut oil; c) about 2% to about 8% by weight of light mineral oil; d) about 2% to about 4% by weight of stearic acid; e) about 0.6% to about 1 .6% by weight of docosanol; f) about 1 % to about 2% by weight of hydrogenated castor oil; g) about 1 % to about 3% by weight of white wax (such as beeswax); h) about 1 % to about 2% by weight of stearyi alcohol; i) about 2.0% to about 5.0% by weight of cetostearyi alcohol; j) about 1.8%
• hydrochloride and m) about 0.1 % to about 0.5% (such as 0.1 %, 0.2%, 0.3%, 0.4%, or 0.5%) by weight of adapaiene.
• composition and/or the foamable are identical to [00252] in some embodiments.
• composition comprises: a) about 40% to about 60% by weight of soybean oil; b) about 20% to about 25% by weight of coconut oil; c) about 2% to about 8% by weight of light mineral oil; d) about 2% to about 4% by weight of stearic acid; e) about 0 6% to about 1 .6% by weight of docosanol; f) about 0.1 % to about 2% by weight of hydrogenated castor oil; g) about 0.1 % to about 3% by weight of a white wax (such as beeswax); h) about 1 % to about 2% by weight of stearyi alcohol; i) about 2.0% to about 5.0% by weight of cetostearyi alcohol; j) about 1 .8% to about 3.3% by weight of myristyl alcohol; k) about 3.0% to about 7.0% by weight of cyciomethicone; I) about 1 % to about 5% (such as 1 %, 1 .5%, 2%, 2.5%,
• composition and/or foamable composition comprises: i) about 50% by weight of soybean oil;
• xiii) about 0.3% by weight of adapalene.
• composition and/or foamable composition is characterized e.g. by comprising Tmh crystals.
• compositions and/or foamable compositions comprising novel Tmh crystals are characterized by one or more of the following markers as illustrated in the examples: a higher final melting temperature; a higher enthalpy, e.g., as measured by DSC (calculated, e.g., as the area by integration under the endothermic curve); a higher intensity of x ray diffraction when measured by small angle x-ray crystallography; a higher number or intensity of Van Der Waals forces e.g., as measured by infrared Spectroscopy; more hydrogen bonds e.g., as measured by Infrared Spectroscopy; a change in the number of hydrophobic interactions, which may lead to a more stable and/or more fluid or f!owabie) formulation; a ram an spectra in the range of about 1400- 1 500 cm-1 with a peak at about 1446 cm-1 having one or two shoulders at about 1465 cm-1 and/or at about 14
• the composition and/or foamable composition of the present disclosure contains a fragrance.
• the fragrance is at a concentration of about 0.1 % by weight to about 1 %, or about 0 2% by weight to about 0.8% by weight.
• the composition is applied as a gel paste, lotion, spray, mask, patch, pomade, ointment, oil, foam or mousse.
• the present disclosure also provides methods of preparing foamabie compositions.
• the method comprises a continuous heating- cooling process.
• the method comprises a holding process.
• the formulation is mixed during each process.
• mixing may optionally be suspended for addition of ingredients.
• a foamabie composition comprising a wax, such as hydrogenated castor oil (such as about 1 -3%
• the foamabie composition further comprises at least one emollient and/or at least one foam adjuvant.
• the foamabie composition further comprises one or more active agents, e.g., a tetracycline antibiotic (such as a minocycline e.g., MCH) and/or a retinoid (such as adapalene). in some embodiments, the formulation does not comprise an active agent.
• the method of preparing a foamabie composition does not comprise a holding process as described herein and instead the melt is cooled in a continuous process.
• sensitive components are added during the cooling process whilst mixing to homogeneity within certain temperature ranges such as about 35 9 C to about 40 9 C or about 24 9 C to about 28 9 G. in one or more embodiments mixing to homogeneity is for up to an hour or about an hour in one or more embodiments mixing to homogeneity is more than an hour (e.g., about 1 -2 hours) in one or more embodiments cooling to a lower temperature continues after the formulation is homogenous.
• the method of preparing a foamabie composition comprises a holding process in some embodiments, the holding process comprises (a) providing a wax, such as hydrogenated castor oil (e.g., about 1 .2%) and mixing it with any other excipients (such as at least one emollient and/or at least one foam adjuvant), and heating the mixture to a temperature sufficient to completely melt the mixture or to a temperature at which a homogenous mixture can be observed ; (b) cooling the mixture to a temperature of about 54 S G, and holding at that temperature for about 1 -1 0 hours, e.g., about 1 -8 hours, or about 1 -5 hours, or about 1 -4 hours, or about 1 -3 hours,; e.g., or about 8 hours, or about 6 hours, or about 5 hours, or about 4 hours, or about 3 hours, or about 2 hours; (c) cooling the mixture to a temperature of about 35 S G to about 40 e G; (d) optionally adding an active agent such as
• one or more process modifications are contemplated which may affect shakabi!ity.
• a holding process comprising holding at about 52 °C for 4 hours and then heating back to about 65 °C results in formulations with improved shakabiiity as compared to those prepared a continuous heating-cooling process, but less shakable than those prepared at holding at about 54 °C for 4 hours (compare Table 17 Example 7, compared to Table 1 1 A in Example 3).
• a continuous process wherein the 1.2% hydrogenated castor is added at 22 °G, followed by a continuous heating cooling procedure results in moderately-shakable or non-shakabie formulations.
• both formulations show DSC thermograms with faded T M 4 and are different from those measured for formulations prepared by a holding process at about 54 °C 4hr. It may be, without being bound by theory, that warming to a higher temperature after a holding period may reduce or eliminate the Tmh crystals which in turn reduces shakabiiity.
• a formulation prepared by holding for 30 min at 55-58 e G is moderately shakable on Day 30 at 25 °G..
• the holding temperature and the holding period may impact the prevention of reduction in Tm4 when adding a wax e.g.
• formulations containing 1.2% hydrogenated castor oil with or without a combination of minocycline and adapalene are prepared by a holding process, where the holding step is performed at different temperatures in some embodiments the holding temperature have a significant impact on the DSC pattern of the tested formulations and TM4 transition in some embodiments formulations prepared at holding temperatures of about 54 °G and about 58 °G may increase TM4 (e.g., to about 69-70 °C). In some embodiments with holding temperatures of about 48 °C and about 66 °C does not produce significant changes in TM4.
• the crystallization process may start prior to the holding.
• crystal nuclei may already have formed, allowing further crystallization seeded by those nuclei to proceed (whereas at a higher holding temperature a different crystallization process may take place).
• higher holding temperatures e.g., about 66 °C which are closer to the melting temperature of hydrogenated castor oil in such formulations, the thermodynamic drive for a structural order of the molecules may be too low or the holding time of 4 hours at this temperature may be too short.
• the holding temperature is about 52 °C, about 53°C, about 54 °C, about 55°C, or about 56 °Cand where TM4 is high in some embodiments, holding temperature of about 54°C and 56°C may result in the presence of more plates and Tmh crystals, whereas holding temperatures of below 54°C and above 56°C may result in the presence of more spherulites that are associated with crystals of lower structural order. In one or more embodiments the holding temperature is between about 54-56°G.
• Tmh crystals are present in formulations prepared by holding temperatures of about 48°C to about 58°C. In some embodiments,
• the relative percentage of area held by these Tmh crystals in formulations prepared by holding temperatures of about 48°G to about 58°G is above 70% compared to the relative percentage area held by the spherulites which is below 30%. in one or more embodiments, the holding temperature is between about 48°C to about 58°G.
• Tmb crystals are bigger than spherulites independent of the bolding temperature in some embodiments, Tmb crystals are higher in number and cover a higher % of the area of the photomicrograph, except for the sample with a 58°C holding temperature, where spherulites and Tmb crystals are present approximately in the same amount and % area.
• Tmh crystals are not present in samples manufactured under 66°C holding, while the samples with holding temperature of 54°C and 56°C exhibit the highest values for Tmh crystals (as measured by crystal count, size, and % Area).
• the effect of bolding temperature on Tmh crystals values is the same for both placebo formulations and formulations with active ingredient.
• a holding temperature for about 4 hours between 52° to 56°C may result in high Tm4 values, which can be indicative of the presence of crystals of a higher structural order. This is confirmed by microscopy where more Tmh crystals are observed as compared to holding at above 58°C or crystallizing below 48°C which reduces the Tm4 values and reduces or eliminates formation of Tmh crystals. Likewise, localized overheating or overheating and then quick cooling may impact on the formation of Tmh crystals.
• a formulation containing 1.2% hydrogenated castor oil, and a combination of minocycline and adapalene, prepared by a holding process with two holding steps first at 54°C for 3 hours and then at 40°C for 3 hours and stored at 40°C for 15 days and 30 days show a slight increase in TM4 compared to formulation prepared with one hold step at 54° C for 4 hours .
• a two-stage holding process may not negatively impact TM4
• the Tmh crystals already formed in the first holding step may remain intact or consolidate during the second holding step.
• a second holding step at a lower temperature may e.g., affect crystallization ot beeswax.
• a formulation containing 1.2% hydrogenated castor oil, and a combination of minocycline and adapalene, prepared by a holding process with two holding steps at 54°C for 3 hours and at 40°C for 3 hours stored at 5°C and 25°C are shakable at all timepoints like formulations prepared with one hold step at 54°C for 4 hours.
• with a two-step process with shorter steps but overall longer holding shakabiiity can go down when stored at 40°C.
• a formulation containing 1 .2% hydrogenated castor oil and combination of minocycline and adapalene is prepared with a bolding step at 54°C for a longer holding process (about 16 hours) results in phase separation although the Tm4 and shakabiiity profile is similar to that of shorter 4 hour holding step.
• formulations with an active agent are prepared using different holding temperatures and holding periods in some embodiments, a formulation prepared with a holding step at 60 °C for 4br and shear is applied when additional components are introduced in some embodiments, formulations are prepared with a holding step at 56 °C for 4hr and 2hr respectively in some embodiments, a formulation is prepared with a shorter holding step at 54 °C (2hr).
• an active agent e.g., comprising a combination of minocycline and adapalene
• shakabiiity is improved with a longer holding step at 56°C (4hr versus 2br) at 40°C after 30 days and a higher TM4 similar to formulations with holding for 4hr at 54°C.
• the TM4 value range is lower (e.g.65.5-66.2°C) where holding Is shorter e.g., for 2br at 56°C.
• the TM4 value range is high (e.g., about 72°C) where holding is for longer e.g., for 4hr at 56°C or for 4hr at 60°C (shear-additional components).
• the TM4 values for 54C 2h and 56C 4hr range Is e.g., about 68-71 °C.
• the TM4 value for 2hr at 56°C is similar to formulations prepared with holding for 4hr at 54° C
• bolding is a single step in some embodiments it is two or more steps in some embodiments each holding step is at about the same temperature in some embodiments each holding is at a successive lower temperature.
• the one or more of the later steps can be at a higher holding temperature, and in some embodiments such higher temperature steps should be below the melting temperature of the waxes in the emollient.
• the period of the holding step or combined holding steps is less than 16 hours, or less than 12 hours or less than 10 hours or less than 8 hours. In some embodiments they are between about 2 to about 8 hours in some
• the proportion of Tmh crystals to spherulites and/or to plates can be modified by varying the holding time and/or the holding temperature. See e.g.,
• the use of high shear during the holding step of the manufacturing process may be detrimental to the formation of Tmh crystals.
• prolonged use of high shear may break or eliminate part or ail of the Tmh crystals or enable part ail of them to form other crystals.
• the presence of high shear for a short period such as 10 mins during or after adding active agent in order to facilitate rapid formation of a homogenous mixture does not appear to have a marked or detrimental effect on the Tmh crystals.
• the use of low shear during the holding step may not prevent the formation of Tmh crystals although prolonged use of low shear may break or eliminate some Tmh crystals or enable some to form other crystals
• the holding process comprises the step of cooling the mixture to a set temperature, e.g., about 54 e G, and holding at that temperature for fixed time, e.g., about 4 hours, i.e., a holding step at the fixed temperature.
• the holding step is a single hold.
• the holding step involves two or more holds (e.g., a first hold and a second hold) in some embodiments the first hold is at a higher temperature (e.g. about 56 e C for a fixed time with mixing) and at the end of the fixed time (e.g. about 3 hours) cooling with mixing to a second hold at a lower temperature (e.g.
• the first hold is at a lower temperature (e.g. about 52 5 C for a fixed time with mixing) and at the end of the fixed time (e.g. about 3 hours) warming with mixing to a second hold at a higher temperature (e.g. about 56 E 'C for a fixed time with mixing) and at the end of that fixed time (e.g. about 3 hours) continuing with step (c ) above.
• a second hold at a higher temperature (e.g. about 56 E 'C for a fixed time with mixing) and at the end of that fixed time (e.g. about 3 hours) continuing with step (c ) above.
• each hold is at a lower temperature than the previous one. in some embodiments the reverse.
• the first is at a higher temperature, the second at a lower temperature and the third at a higher temperature, which is higher than the second but is lower or no higher than the first in some embodiments the first is at a lower temperature, the second at a higher temperature and the third at a lower temperature, which is lower than the second but is lower or no higher than the first.
• the holding step is done at about 48-86 e C, e.g., about 52-58 Q C. In some embodiments, the holding step is done at about 48 9 C to about 60 e G, for example, about 48 S G to about 59 S C, about 58 S G, about 57 S G, about 56 S C, about 55 9 C, about 54 e C, about 53 e C, about 52 S C, about 51 9 C, about 50 9 C; or about 49 9 C to about 59 9 C, about 58 9 C, about 57 9 C, about 56 S G, about 55 9 C, about 54 9 C, about 53 B G, about 52 S G, about 51 e G, or about 50 9 G or can be a range between any two figures listed in this paragraph, such as 54-58 9 C.
• the holding step is conducted for about 1 to 72 hours, e.g., about 66 hours, about 60 hours, about 54 hours, about 48 hours, about 42 hours, about 1 to 38 hours, about 1 to 30 hours, about 1 to 24 hours, about 1 to 18 hours, about 1 to 16 hours, about 1 to 12 hours, about 1 to 10 hours, about 1 to 8 hours, about 1 to 6 hours, about 1 to 5 hours, about 1 to 4 hours, about 1 to 3 hours, about 1 to 2 hours, about 2 to 4 hours, or about 4 to 6 hours.
• the holding step is conducted tor about 1 -12 hours. In some other embodiments the holding step may be longer.
• the holding step may allow for minor temperature fluctuation during the holding period.
• the holding step allows the temperature to drop or rise slowly, e.g. a rise or a drop in
• the holding step comprises a fixed temperature holding step followed by a gradient holding step in some embodiments the holding step comprises a gradient holding step followed by a fixed temperature holding step.
• mixing using high shear or other methods that can input heat or energy into the crystals e.g., as they pass through a homogenizer mixer may be avoided or ameliorated or used only for a relatively short period and/or at lower speed so that the Tmh crystals are not substantially reduced or eliminated in the composition.
• the method comprises mixing a wax (e.g.
• the method comprises performing a holding process for a mixture of oil(s) and each of the multiple waxes separately in one or more embodiments the method comprises performing a separate holding process for a mixture of oil(s) and foam adjuvants and/or other excipients in one or more embodiments, the method comprises performing a separate holding process for mixtures of oil(s) and each of multiple waxes and for a mixture of oil(s) and the foam adjuvants and/or other excipients followed by mixing the components and performing holding of the resultant mixture.
• oils e.g. soybean oil
• Also provided herein are methods of preparing a foamable composition comprising a tetracycline antibiotic, at ieast one emollient, at least one wax e.g., hydrogenated castor oil; or comprising a tetracycline antibiotic, at least one emollient, at Ieast one foam adjuvant, and a wax e.g., hydrogenated castor oil.
• the method comprises (a) mixing at ieast one emollient, at Ieast one foam adjuvant, and a wax such as hydrogenated castor oil, and heating the mixture to a temperature sufficient to completely melt the mixture or to a temperature at which a homogenous mixture can be observed; (b) cooling the mixture to a temperature of about 54 S G, and holding at that temperature for about 4 hours; (c) cooling the mixture to a temperature of about 35 B C to about 40 B C; (d) adding the active agent such as a tetracycline antibiotic and/or an emollient such as
• cyclomethicone to the mixture; (e) cooling the mixture to a temperature of about 24 B G to about 28 B G; (f) optionally adding an additional active agent such as a retinoid to the mixture; (g) cooling the mixture to a temperature of about 22 S G to about 28 B C; and (b) stirring the mixture for up to 24 hours at a temperature of about 20 B C to about 24 e G.
• the process comprises the step of cooling the mixture to a set temperature, e.g., about 54 B C, and holding at that temperature for fixed time, e.g., about 4 hours in some embodiments, the process comprises the step of cooling the mixture to a set temperature, e.g., about 54 B G, and holding at that temperature for fixed time, e.g., about 2 hours. In some embodiments, the process comprises the step of cooling the mixture to a set temperature, e.g., about 56 B C, and holding at that temperature for fixed time, e.g., about 6 hours in some embodiments, the process comprises a holding step (e.g., as described above and herein).
• a holding step e.g., as described above and herein.
• the mixture is cooled to room
• the cooling is with mixing. In some embodiments it is cooled to about 20 S C to about 28 B C, or about 22 S C to about 28 e C, or about 24 e C to about 28 e C, or about 20 9 C to about 26 9 C, or about 20 9 C to about 25 9 C, or about 20 9 C to about 24 9 C, or about 20 9 C to about 23 9 C, or about 20 e G to about 22 9 G, or about 21 e G to about 26 9 G about 22 E 'C to about 26 S C, or about 23 S G to about 26 e G, or about 24 9 G to about 26 9 G, about 21 S G to about 25 B C, or about 22 9 C to about 25 S C, or about 23 Q G to about 25 Q G, or about 22 Q G to about 24 S G, or about 20 B G, or about 21 9 C, or about 22 9 C, or about 23 B G, or about 24 B C , or about 25 e G, or about 26 B G, or about 27 B G, or about 28
• homogeneity is for up to an hour or about an hour. In one or more embodiments mixing to homogeneity is more than an hour (e.g., about 1 -2 hours) in some embodiments the formulation is then further subjected to cooling to about 22 9 C to about 28 9 C, or about 22 e C to about 26 e C, In some further embodiments it is to about 22 e G to about 24 9 G, or about 20 B C to about 26 B C, In some embodiments the formulation is then subjected to a mixing step for about 3 up to 24 hours.
• the mixing step that follows cooling may start at about 28 9 G with cooling continuing to between about 20 B C to about 24 B C and then maintaining the temperature in that range in some embodiments the mixing step that toliows cooling may start at about 27 9 C, or about 26 B C, or about 25 9 C with cooling continuing to between about 20 9 C to about 24 B C and then maintaining the temperature in that range in some embodiments the mixing step that follows cooling may start at about 24 B C, or at about 23 B C, at about 22 S C, with the temperature being maintained in the range of about 20 B C to about 24 B G. In some embodiments the temperature is maintained in the range of about 20 B C to about 26 B C In some embodiments the temperature is maintained at about 20 B G, or about 21 B G, or about 22 g C, or about 23 g C, or about 24 g C.
• Also provided herein are methods of preparing a foamabie composition comprising a tetracycline antibiotic, a retinoid, at least one emollient, at least one foam adjuvant, and a wax e.g., hydrogenated castor oil.
• the method comprises (a) mixing at least one emollient, at least one foam adjuvant, and hydrogenated castor oil, and heating the mixture to a temperature sufficient to completely melt the mixture; (b) cooling the mixture to a temperature of about 54 e C, and holding at that temperature for about 4 hours; (c) cooling the mixture to a temperature of about 35 S G to about 40 S G; (d) adding the tetracycline antibiotic and/or cyclomethicone, to the mixture; (e) cooling the mixture to a temperature of about 24 5 C to about 28 5 C; (f) adding the retinoid to the mixture; (g) cooling the mixture to a temperature of about 22 g C to about 24 S G; and (h) stirring the mixture for up to 24 hours at a temperature of about 20 S G to about 26 S G in some embodiments, the process comprises the step of cooling the mixture to a set temperature, e.g., about 54 S G, and holding at that temperature for fixed time, e.g , about 4
• the process comprises the step of cooling the mixture to a set temperature, e.g., about 54 g C, and holding at that temperature for fixed time, e.g., about 2 hours in some embodiments, the process comprises the step of cooling the mixture to a set temperature, e.g., about 56 S G, and holding at that temperature for fixed time, e.g., about 6 hours in some embodiments, the process comprises a holding step (e.g., as described herein).
• the method further comprises a step of pressurizing the mixture with a propellant, e.g., Propellant AP-7Q, in an aerosol container.
• a propellant e.g., Propellant AP-7Q
• foamabie compositions are packed in a container with an outlet valve e.g., aerosol canister.
• outlet valve e.g., aerosol canister.
• both the minocycline and the foamabie compositions containing minocycline can be manufactured under current Good Manufacturing Principles (cGMP) conditions.
• the foamabie composition is provided in aluminum aerosol canisters mounted with valve and actuator in some embodiments the size of the cannister is determined by the dose to be delivered in some embodiments the cannister may provide doses for 3 months, or 2 months, or 1 month, or for one or two weeks in some embodiments the cannister may be a single dose cannister.
• a canister is filled with 35 g of product and 4 2 g of propellant.
• the canister is filled with 15gr product and 1 .8gr propellant.
• the canister is filled with 6gr product and 0.72gr propellant.
• the canister is filled under nitrogen atmosphere. Upon actuation of the canister an aliquot of quality foam is released.
• the composition and/or foamabie composition comprises crystals.
• hydrogenated castor oil and/or other excipients such as other waxes (alone or combinations) may form crystals or co-crystals within the composition and/or foamabie composition and/or released foam, that have different shapes, e.g., nonuniform, rod, plate, needle, or sphere.
• Formulation components e.g., waxes, that are solid at room or body temperatures, may form microcrystais distributed homogenously within the foamabie composition in some embodiments, crystals, e.g., microcrystais or large crystals, are distributed homogenously within the foamabie composition.
• the foamabie compositions and the methods to prepare them described herein may affect the shapes of the crystals within the compositions.
• the shapes of the crystals in turn may affect the stability, viscosity, rheology, sebum softening/breakdown/liquification, melting properties, and/or shakability of the compositions, foamabie compositions, and/or foams.
• This disclosure is based partly on the surprising discovery that altering the crystal fingerprint of the formulation, e.g., crystal fingerprint of the components that are solid at body temperature, e.g., waxes or hydrogenated castor oil, can improve the stability, usability, fiowabiiity, shakability of the foamabie compositions and/or foams.
• the formulations provided herein may comprise a mixture of components, each with its own melting temperature and crystallization profile.
• each component of the formulations provided herein can affect the crystallization profiles, melting temperature, and/or crystallization fingerprint of other components within the formulation in one or more embodiments, the combination of different excipients and/or active agents at different amounts in the formulations provided herein forms crystals with a unique crystallization fingerprint.
• the crystallization fingerprint may affect the properties of the
• formulations e.g. sebum liquification, fluidity, shakability, and stability.
• a formulation provided herein has Tmh crystals in some embodiments, even a relatively small proportion of such crystals, relative to the overall composition, may surprisingly improve stability (e.g., storage stability for a period of days, months, years) at room temperature.
• stability e.g., storage stability for a period of days, months, years
• such a formulation provides surprisingly improved stability even when the formulation comprises an active agent or other excipient which can destabilize the formulation and/or interfere with shakabiity (e.g., adapalene).
• Such formulations with T h cyrstals may also improve the ability of the formulation to melt sebum and thereby increase penetration.
• Tmh crystals are formed from hydrogenated castor oil (or other waxes) during a holding step process disclosed herein in some embodiments, Tmh crystals are co-cyrstals of hydrogenated castor oil (or other waxes) and other excipients during a holding step process disclosed herein.
• the formulations disclosed herein comprise crystals with a crystal fingerprint that is associated with preparation of the formulation by a holding process.
• foamab!e formulations comprising propellant comprise crystals with a crystal fingerprint that is associated with preparation of the formulation by a holding.
• foam formulations not comprising propellant i.e., after foam formation
• a crystal fingerprint in a foamable formulation is also present in the resultant foam.
• some or all (e.g., a majority) of the crystals in a composition, foamable composition, and/or foam are Tmh crystals (e.g., crystals having nonuniform shapes formed during a holding process method disclosed herein) in some embodiments, some or ail the crystals are spheruiites. in some embodiments, some or all the crystals are plate shaped. In some embodiments, some or all the crystals are needle shaped. In some embodiments, some or all the crystals are rod-shaped in some embodiments, the crystals have a combination of shapes, e.g., more fhan one of nonuniform, rod, plate, needle, sphere, or spherulite shapes.
• a majority of the crystals are nonuniform, e.g., not spheroid. In some embodiments, a majority of the crystals comprise nonuniform shapes. In some embodiments, a majority of the crystals comprise spherulite shapes. In some embodiments, a majority of the crystals comprise plate shapes in some embodiments, a majority of the crystals comprise needle shapes. In some embodiments, a majority of the crystals comprise rod shapes. In some
• less than a majority of the crystals comprise spherulites.
• the crystals in a foamable composition comprise nonuniform shapes to a greater degree than in a comparable composition and/or foamable composition or foam produced by a process that does not comprise a hold step, e.g , a step of cooling the mixture to a temperature of about 50-60 S C and maintaining the mixture at the temperature for about 1 -1 2 hours.
• the ratio of Tmh crystals to spherulites and plates is about 100:1 , e.g., about 95:1 , about 90:1 , about 85:1 , about 80:1 , about 75:1 , about 70:1 , about 65:1 , about 60:1 , about 55:1 , about 50:1 , about 45:1 , about 40:1 , about 35:1 , about 30:1 , about 25:1 , about 20:1 , about 15:1 , about 10:1 , about 5:1 , about 1 :1 , about 1 :5, about 1 : 10, about 1 :15, about 1 :20, about 1 :25, about 1 :3G, about 1 :35, about 1 :40, about 1 :45, about 1 :50, about 1 :55, about 1 :6G, about 1 :65, about 1 :70, about 1 :75, about 1
• the ratio is more than any of the aforesaid. In some other embodiments the ratio is less than any of the aforesaid, By way of example, in an embodiment more than 100:1 , and in another embodiment less than 100:1 .
• the ratio of Tmh crystals to spherulites is about 100:1 , e.g., about 95:1 , about 90:1 , about 85:1 , about 80:1 , about 75:1 , about 70: 1 , about 65:1 , about 60:1 , about 55:1 , about 50:1 , about 45: 1 , about 40: 1 , about
• the ratio is more than any of the aforesaid. In some other embodiments the ratio is less than any of the aforesaid, By way of example, in an embodiment more than 1 00:1 , and in another embodiment less than 100:1 .
• the Tmh crystals formed In formulations prepared by a holding process have an average cross-sectional area of about 40 to about 150 pm 2 , or about 50 to about 150 pm 2 .
• the Tmh crystals formed in formulations prepared by a holding process have an average cross-sectional area of about 50-80 pm 2 on average (e.g., about 55-70 pm 2 on average, e.g., about 61 -63 pm 2 on average).
• the Tmh crystals formed in formulations prepared by a holding process are larger than the spheruiites observed in formulations prepared by a continuous heating-cooling process.
• cross- sectional area is measured at the largest cross-sectional point in a crystal.
• the Tmh crystals prepared by a holding process occupy about or at least about 15% of the area measured in a
• the percentage of fhe area occupied by the Tmh crystals is compared to that for spheruiites.
• the Tmh crystals occupy by area about 16%, about 17%, about 18%, about 19%, about 20%, about 21 %, about 22%, about 23% about 24%, about 25%, about 26%, about 27%, about 28%, about 29% %, about 30%, about 31 %, about 32% %, about 33%, about 34%, or about 35% of the area measured. In some embodiments the Tmh crystals occupy about e.g., about 15% to about 35%, about 20% to about 34%, about 25% to about 33%, or about 30% to about 33% of the area measured.
• the percentage area occupied by spheruiites is measured using one or more of the methods discussed above for measuring the percentage area of Tmh crystals in a formulation sample. In one or more
• spheruiites observed in formulations prepared by a continuous heating-cooling process have an average area of about 24-25 pm 2 .
• the spheruiites observed in formulations prepared by a continuous heating-cooling process are on average smaller than the Tmh crystals formed in formulations prepared by a holding process, e.g., having cross-sectional area of about 50-80 pm 2 on average (e.g., about 55-70 pm 2 on average, e.g., about 61 -63 pm 2 on average).
• the spheruiites occupy about 20- 25%, e.g., about 22-23% of the area measured in a sample.
• the percentage area occupied by plates is measured using one or more of the methods discussed above for measuring the percentage area of Tmb crystals in a formulation sample. In one or more
• crystals with plate structures are present in a formulation disclosed herein.
• plates are observed whether the composition is prepared according to a holding or according to a continuous process in some embodiments, crystals with plate structures are smaller on average in formulations prepared by a continuous heating-cooling process (about 12-13 pm 2 on average) compared to those prepared by a holding process (about 15-19 pm 2 on average).
• crystals with plate structures have an average size of about 10-20 pm 2 , e.g., about 12-13 pm 2 , in formulations prepared by a continuous heating-cooling process.
• crystals with plate structures have an average size of about 15-19 pm 2 in formulations prepared by a holding process.
• the holding process does not substantially change the crystal polymorph of a formulation disclosed herein in one or more embodiments, the holding process forms a new polymorph that is very similar, e.g., having subtle differences, to the polymorph formed by a process other than a holding process.
• the crystals in a formulation prepared with a hold step have a different microstructure as compared to crystals formed by a process ofher than a holding process in some embodiments there is no observed change in polymorph by x-ray powder diffraction but there is in crystal structure.
• the holding process changes crystal morphology, e.g., changes in crystai microstructure to alter the shape and/or concentration of T h crystals, but does not change crystal polymorph, e.g., crystal lattice.
• the method described herein of preparing a foamabie composition produces a foam that comprises more crystals with nonuniform shapes as compared to other structures, e.g., fibers, needles, plates, rods, or a combination thereof, particularly crystals or microcrystals with regular shapes, e.g., spheruiites, as measured by transmission electron microscopy.
• the method described herein of preparing a foamabie composition produces a foam that comprises more crystals with non uniform shapes, as measured by light microscopy, transmission electron microscopy (TEM),
• DSC Differential Scanning Calorimetry
• small angle X-Ray scattering small angle X-Ray scattering
• wide angle X-Ray scattering wide angle X-Ray scattering
• Field Emission Scanning Electron Microscopy and Energy
• DSC Dispersive X-ray Spectroscopy
• FE-SEM/EDS Dispersive X-ray Spectroscopy
• X-ray powder diffraction is used.
• DSC Differential scanning calorimetry
• Tm phase transitions
• the compositions provided herein comprise Tmh crystals with a DSC pattern comprising a phase transition temperature TM4 of about 50-80 °C, e.g., above 60 °C, or above 64°C, e.g., 68-69 e G or e.g., about 64-72 g C, e.g., about 68-72 g C.
• the compositions provided herein comprise Tmh crystals with a DSC pattern comprising a phase transition temperature TM4 that is about 3 g C or about 4 e C, or about 5 g G, or about 6 g C higher than that of a formulation prepared in a continuous heating-cooling process.
• the use of HCO contributes to the higher TM4, e.g., alone or in combination with a holding process step.
• Tmh crystals in a formulation disclosed herein are measured by small angle X-ray scattering.
• the average intensity as measured by small angle X-ray scattering for a formuiation prepared by a holding process is about 0.031 cm 1 versus about 0.014 cm 1 for a formulation prepared by a continuous heating-cooling process.
• the average intensity as measured by small angle X-ray scattering of a formulation prepared by a holding process is more than 2 times higher, more than 2.5 times higher , more than 3 times higher, more than 3.5 times higher, more than 4 times higher, more than 4.5 times higher, more than 5 times higher, more than 5.5 times higher, more than 6 times higher, more than 6.5 times higher, more than 7 times higher, more than 7.5 times higher, more than 8 times higher, more than 8.5 times higher, more than 9 times higher, more than 9.5 times higher, or more than 10 times higher than that of a formulation prepared by a continuous heating-cooling process.
• a“unit cell” refers to the smallest repeating unit in a crystal.
• Tmh crystals have stronger interactions between unit cells than regular-shaped crystals, e.g., rods, plates, needles in some
• Tmh crystals have unit cells that are tangled fibers.
• the method comprises: (a) formulating a mixture comprising at least one emollient, at least one foam adjuvant, and a wax, such as hydrogenated castor oil; (b) heating the mixture to a first temperature sufficient to completely melt the at least one emollient, the at least one foam adjuvant, and wax; (c) cooling the mixture in a nonlinear fashion that comprises holding at a second temperature; and (d) stirring the mixture at the second temperature; wherein the first temperature is higher than the second temperature.
• the first temperature is about 10-90 9 C higher than the second temperature.
• the first temperature is about 10-60 E 'C higher than the second temperature. In some embodiments, the first temperature is about 10-40 e G higher than the second temperature. In some embodiments, the second temperature is about 45-70 9 C, e.g., about 49 9 C, about 50 Q C, about 51 Q G, about 52 S C, 53 E 'C , about 54 9 C, about 55 B C, about 56 S G, about 57 e G, 58 S C , about 59 e G, about 60 e C, about 61 , about 62 9 C, about 63 9 C, about 64 e C, or about 65 e C.
• the second temperature is about 45-70 9 C, e.g., about 49 9 C, about 50 Q C, about 51 Q G, about 52 S C, 53 E 'C , about 54 9 C, about 55 B C, about 56 S G, about 57 e G, 58 S C , about 59 e G, about 60 e C, about 61 , about 62 9
• holding at a second temperature is for at least about 20 minutes to about 24 hours, e.g., about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 1 1 hours, about 12 hours, about 13 hours, about 14 hours, about 16 hours, about 18 hours, about 20 hours, or about 22 hours.
• Tmh wax crystals obtained from a holding process are present in the ioamab!e formulations provided herein before addition of propellant
• the Tmh wax crystal are present in the foamabie formulations comprising propellant provided herein.
• the Tmh crystals are present in the resultant foam obtained from the foamabie formulations provided herein in one or more embodiments the Tmh crystals are present in the foamabie formulations before and after addition of propellant in one or more embodiments the Tmh crystals are present in the foamabie formulations and in the resultant foam.
• Sebum is a light yellow, oily substance that is secreted by the sebaceous glands that help keep the skin and hair moisturized.
• the ability of the active agents in the foam or foamabie compositions to be absorbed by the skin may depend on their ability to mix with sebum and/or penetrate into the pilosebaceous unit.
• compositions, and or foamabie compositions and or foams described herein surprisingly reduce the melting temperature of sebum and or aid its dissolution, liquefaction or break-up.
• dissolution or liquefaction of the sebum may decrease the viscosity of sebum at skin temperature, increase the diffusion coefficient and provide for better ability of the active ingredient to penetrate into pilosebaceous ducts.
• the formulations disclosed herein may help to open up the pores and provide deliver therapeutic agents, e.g., minocycline and adapaiene, into pilosebaceous ducts for treafment of inflammatory and non inflammatory lesions.
• the crystal fingerprint present in formulations prepared by a holding process comprises Tmh crystals that are unique and may have reduced crystal interaction with other components of the formulation, resulting in a higher formulation f!owabi!ity and different formulation melting temperatures and enthalpy, that may Improve the composition’s ability to dissolve or break down sebum.
• the foamable composition is capable of softening sebum, which in turn may help increase skin penetration.
• a foamable formulation prepared by a holding process reduces sebum melting point to a greater extent than an oil in water emulsion.
• the foamable composition provided herein reduces sebum melting point to a greater extent than a formulation prepared in a continuous heating-cooling process.
• a foamable composition prepared in a holding process reduces sebum melting point to a greater extent than a formulation prepared in a continuous heating-cooling process in one or more embodiments, the foamable composition provided herein reduces sebum melting point temperature by about 2 °C, about 3 °C, about 4 °C, about 5 °C, about 6 °C, about 7 °C, or about 8 °C.
• the melting temperature of a 1 :1 mixture of sebum and a foamab!e composition disclosed herein is 10% lower than the melting temperature of sebum alone. In some embodiments, the melting temperature of a 1 :1 mixture of sebum and the foamable composition is 20% lower than the melting temperature of sebum alone. In some embodiments, the melting temperature of a 1 :1 mixture of sebum and the foamable composition is 30% lower than the melting temperature of sebum alone. In some embodiments, the melting temperature of a 1 :1 mixture of sebum and the foamable composition is 40% lower than the melting temperature of sebum alone.
• the melting temperature of a 1 :1 mixture of sebum and the foamable composition is 50% iower than the melting temperature of sebum alone. In some embodiments, the melting temperature of a 1 :1 mixture of sebum and the foamable composition is 60% !ower than the melting temperature of sebum alone. In some embodiments, the melting temperature of a 1 :1 mixture of sebum and the foamable composition is 70% iower than the melting temperature of sebum alone. In some embodiments, the melting temperature of a 1 :1 mixture of sebum and the foamable composition is 80% iower than the melting temperature of sebum alone.
• the melting temperature of a 1 :1 mixture of sebum and the foamable composition is 90% Iower than the melting temperature of sebum alone. In some embodiments, the melting temperature of a 1 :1 mixture of sebum and the foamable composition is 1 00% iower than the melting temperature of sebum alone.
• the melting temperature of a 1 :1 mixture of sebum and a foamable composition disclosed herein prepared by a holding process is Iower than that of the same composition prepared by a continuous heating-cooling process.
• the melting temperature of a 1 :1 mixture of sebum and a foamable composition disclosed herein prepared by a holding process is about 10% Iower, about 15% lower, about 20% iower, about 25% Iower, about 30% Iower, about 35% iower, about 40% Iower, about 45% Iower, about 50% iower, about 55% Iower, about 60% Iower, about 65% Iower, about 70% iower, about 75% Iower, about 80% Iower, about 85% iower, about 90% iower, about 95% Iower, or about 100% iower than the melting temperature of a 1 :1 mixture of sebum an a foamable composition prepared by a continuous heating-cooo
• the melting point of the 1 :1 mixture of sebum and the foamable composifion is between about 30.0 °C and 31 .0 °C in some embodiments, wherein the melting point of the 1 :1 mixture of sebum and the foamable composition is between about 31 .0 °C and 32.0 °C. In some embodiments, wherein the melting point of the 1 :1 mixture of sebum and the foamable composition is between about 32.0 °C and 33.0 °C. In some embodiments, wherein the melting point of the 1 :1 mixture of sebum and the foamable composition is between about 33.0 °C and 34.0 °C.
• the melting point of the 1 :1 mixture of sebum and the foamable composition is between about 34.0 °C and 35 0 °G. In some embodiments, wherein the melting point of the 1 :1 mixture of sebum and the foamabie composition is between about 35.0 °C and 36.0 °C. In some embodiments, wherein the melting point of the 1 :1 mixture of sebum and the foamabie composition is between about 36.0 °C and 37.0 °C. in some embodiments, wherein the melting point of the 1 :1 mixture of sebum and the foamabie composition is between about 37.0 °C and 38.0 °C.
• the melting point of the 1 :1 mixture of sebum and the foamabie composition is between about 38.0 °C and 39.0 °C. in some embodiments, wherein the melting point of the 1 : 1 mixture of sebum and the foamabie composition is between about 39.0 °C and 40.0 °C. In some embodiments, wherein the melting point of the 1 :1 mixture of sebum and the foamabie composition is between about 40.0 °C and 41 .0 °C. In some embodiments, wherein the melting point of the 1 :1 mixture of sebum and the foamabie composition is between about 41.0 °C and 42.0 °C. in some embodiments, wherein the melting point of the 1 :1 mixture of sebum and the foamabie composition is between about 42.0 °C and 43.0 °C.
• Foam is advantageous in the topical treatment of skin diseases since it is light and easy to apply and collapses and spreads with a minor mechanical force like a simple rub.
• drug delivery in the form of foam can also cover a larger surface area of application while also facilitating better product application in areas where conventional topical products cannot be as effective.
• Foam absorbs rapidiy-without the need of repeated rubbing-which is helpful and important for treatment of damaged or irritated skin, sores, and lesions. As the composition is absorbed quickly, this can contribute to a positive treatment effect by the vehicle alone, or when in combination with the active agent, a higher percentage effect by the active agent may be observed
• Stable foam which breaks upon application of mild shear force is extremely advantageous in the topical treatment of skin diseases. It can be applied directly onto skin or hands of the patient without collapsing. The foamabie
• compositions described herein facilitate easy application and even distribution of the active agent, thereby improving treatment convenience.
• the formulation packaged into an aerosol container is devoid of any contact with air, light, or any other form of contamination (e.g., moisture) as it is a completely sealed system throughout the life of the product.
• contamination e.g., moisture
• the composition and/or foamable compositions described herein are filled info aerosol cans or canisters and pressurized with a propellent.
• the aerosol can or canister may comprise an outlet valve, that when actuated, releases the foamable composition from the can or canister and converts it into a foam composition.
• the aerosol or canister comprises a nozzle for directing a foamable composition from the inside to the outside of the canister.
• the foamable compositions disclosed herein can be applied to the target site as a gel or a semi-solid gel or ointment or foam or mousse.
• the foamable compositions can be applied as a liquid gel or as a collapsed foam.
• the composition is thixotropic.
• the foamable formulation shows a reduction in viscosity with time when subjected to constant shear force in some embodiments, after the foamable formulation is allowed to rest for a period of time, the viscosity increases again.
• the foamable composition is a solid or semi-solid composition or gel prior to adding a propellant.
• the foamable composition is a gel or a liquid.
• the propellant is miscible with the foamable composition.
• the propellant dilutes the foamable composition.
• the foamable composition forms a breakable foam with good to excellent quality when dispensed. Since the propellant evaporates during dispensing, the resulting foam is pharmaceutically equivalent to the foamable composition (prior to adding the propellant). Thus, upon collapse, the foam is compositionaily similar or identical to the foamable composition. This is an advantage as the drug development process, including toxicology studies and clinical trials, need only be conducted for either the foamable composition or the foam and not for both.
• the foamable composition when packaged in an aerosol container to which is added a liquefied or compressed gas propellant, the foamable composition provides upon release from the container a breakable foam of at least good quality that breaks easily upon application of mechanical force.
• the foamable composition is thermally stable at skin temperature (e.g., about 37 °C).
• the foamable composition is filled info an aerosol can or canister and pressurized with a propellant.
• a foamable composition comprises: (a) about 60% to about 95% by weight of at least one emollient; (b) about 1% to about 2% by weight of hydrogenated castor oil; (c) about 0.1% to about 5% by weight of a tetracycline antibiotic ⁇ e.g., minocycline or minocycline HCI); (d) about 0.1% to about 1% by weight of a retinoid; and (e) about 5% to about 15% by weight at least one foam adjuvant.
• a tetracycline antibiotic ⁇ e.g., minocycline or minocycline HCI
• a foamable composition comprises: (a) about 60% to about 95% by weight of at least one emollient; (b) about 1% to about 2% by weight of hydrogenated castor oil; (c) about 0.1% to about 5% by weight of a tetracycline antibiotic (e.g., minocycline or minocycline HCI); (d) about 0.1% to about 1% by weight of a retinoid; (e) about 5% to about 15% by weight at least one foam adjuvant; and (f) about 1% to about 5% by weight at least one wax foam adjuvant.
• a tetracycline antibiotic e.g., minocycline or minocycline HCI
• compositions provided or described herein comprise a carrier and a propellant in one or more embodiments, the carrier comprises a foamable composition provided or described herein.
• the foamable composition is a gel, paste, lotion, spray, mask, patch, pomade, ointment, oil, foam or mousse in one or more embodiments, the foamable composition is hydrophobic. In one or more
• the foamable composition comprises hydrophobic oils and waxes in one or more embodiments, the foamable composition comprises fatty alcohols. In one or more embodiments, the foamable composition comprises hydrophobic oils and fatty alcohols. In one or more embodiments, the foamable composition comprises fatty acids in one or more embodiments, the foamable composition comprises hydrophobic oils and fatty acids.
• the foamable composition comprises a gelled oil.
• the gelled oil is a gelled mineral oil.
• the gelled mineral oil is a VERSAGEL®.
• VERSAGELs® are gelled oils or emollients that can come in different product forms including, for example, the VERSAGEL ⁇ m, VERSAGEL® p, VERSAGEL® r, and VERSAGEL ⁇ s series, and provide various viscosity grades. There are also VERSAGELs ⁇ with isohexadecane, or with isododecane, or with hydrogenated polyisobutene, or with isopropyipa!mitate.
• VERSAGEL® 750 m. In an embodiment, it is VERSAGEL® 200 m. In an embodiment, it is VERSAGEL® 500 m. in an embodiment, it is VERSAGEL® 1600 m.
• VERSAGEL® m contains a mixture of mineral oil plus one or two or more of e.g., Ethylene/Propylene/Styrene Copolymer plus e.g., Butylene/Ethylene/Styrene Copolymer plus e.g., butylated hydroxyl toluene or similar gelling agents.
• the stability of a foam composition depends on the formulation of the composition.
• the stability of a foam may be determined by the time it takes for a foam to collapse, e.g., to 50% of its starting height.
• the foam composition has a collapse time of at least about 90 seconds in some embodiments, the foam composition has a collapse time of at least about 120 seconds.
• the foam composition has a collapse time of at least about 150 seconds.
• the foam composition has a collapse time of at least about 180 seconds.
• the foam composition has a collapse time of at least about 240 seconds. In some embodiments, the foam composition has a collapse time of at least about 300 seconds. In some embodiments, the foam composition has a collapse time of at least about 100 seconds, at least about 1 10 seconds, at least about 130 seconds, at least about 140 seconds, at least about 160 seconds, at least about 170 seconds, at least about 190 seconds, at least about 200 seconds, at least about 210 seconds, at least about 220 seconds, at least about 230 seconds, at least about 250 seconds, at least about 260 seconds, at least about 270 seconds, at least about 280 seconds, or at least about 290 seconds.
• the drainage time is the time it takes for the foam to degrade in quality, as defined by some measure, e.g., criteria as described herein.
• a slow drainage is a drainage of about or greater than 180 sec.
• foam drainage is at least about (i.e about or more than) 90 seconds, at least about 120 seconds, at least about 150 seconds, at least about 240 seconds, or at least about 300 seconds.
• the foamable composition has been packaged in an aerosol can or canister, it may be beneficial for a user to shake the canister before actuating the valve and releasing the foam. Shaking the canister before use homogenizes and disperses the propellant and foamable compositions within. To this end, it is also desirable for a user to be able to feel or hear the presence of the contents when the filled pressurized canister is shaken.
• “shakability” refers to the degree to which the user is able to feel or hear the presence of the foamable composition when the filled pressurized canister is shaken. Shaking is done with mild to normal force without vigorous or excessive force.
• the foamable composition When the user cannot sense the motion of the contents during shaking the foamable composition may be considered to be non-shakab!e. When the user can moderately sense the motion of the contents during the shaking, the foamable composition is considered moderately shakable. When the contents are fiowabie during shaking, the product is considered shakable.
• a composition and/or a foamab!e composition with improved fluidity This in turn can lead to an improved shakability.
• the foamable composition has improved shakability.
• the foamable composition comprising hydrogenated castor oil has improved shakability, compared to foamable compositions not comprising hydrogenated castor oil.
• the foamable composition comprising hydrogenated castor oil has similar shakability, on Day 0 and Day 15 at all temperatures tested, compared to foamable compositions comprising paraffin wax.
• the foamable composition comprising hydrogenated castor oil has improved shakability, compared to foamable compositions comprising a paraffin wax.
• the foamable composition comprising a paraffin wax has improved shakability compared to foamable compositions comprising hydrogenated castor oil.
• the foamable composition comprising a wax has improved shakability compared to foamable compositions that do not comprise a wax.
• the foamable composition comprising a wax e.g., hydrogenated castor oil has reduced shakability compared to foamable compositions that do not comprise a wax.
• the foamable composition is shakabie for at least 1 day, at least 14 days, at least 15 days, at least 30 days, at least 60 days, at least 90 days, or at least 180 days when stored at 5 °C.
• the foamable composition is shakabie for at least 12 months, or at least 18 months, or at least 24 months, or at least 30 months, or at least 36 months when stored at 5 °C. In some embodiments, the foamable composition is shakabie for at least 1 day, at least 14 days, at least 15 days, at least 30 days, at least 60 days, at least 90 days, or at least 180 days when stored at 25 °C. in some embodiments, the foamable composition is shakabie for at least 10 months, or at least 12 months, or at least 18 months, or at least 24 months when stored at 25 °C.
• the foamable composition is shakabie for at least 1 day, at least 14 days, at least 15 days, at least 30 days, at least 60 days, at least 90 days, or at least 180 days when stored at 40 °C. In some embodiments, the foamable composition is moderately shakabie for at least 12 months, or at least 18 months, or at least 24 months, or at least 30 months, or at least 36 months when stored at 5 °C. In some embodiments, the foamable composition is moderately shakabie for at least 12 months, or at least 18 months, or at least 24 months, or at least 30 months, or at least 36 months when stored at 25 °C. In some embodiments, the foamable composition is moderately shakabie for at least 12 months, or at least 18 months, or at least 24 months, or at least 30 months, or at least 36 months when stored at 40 °C.
• the ability of the foamable composition to flow may also affect the passage of the composition upon release from the aerosol container.
• a foamable composition can block a valve or a nozzle of the aerosol container, which is undesirable.
• the foamable composition is flowab!e and does not block a valve of the aerosol container in some embodiments, the foamable composition does not block a valve of the aerosol container for at least 1 day, or at least 10 days, or at least 15 days, or at least 30 days, or at least 60 days, or at least 90 days, or at least 180 days at room
• the formulation is flowab!e at room temperature for at least about 3 months, at least about 6 months, at least about 9 months, at least about 12 months, at least about 8 months, or at least about 24 months.
• a non-shakable formulation has some f!owablility and allows formation of a foam of quality (e.g. good quality)
• a foamabie composition described herein is provided in an aerosol or canister that comprises a nozzle that directs the
• a foamabie composition described herein does not clog the nozzle or valve of the canister.
• a foamabie composition produced by a holding process does not result in dogging of the nozzle of the canister in some embodiments, a foamabie composition produced by a holding process results in substantially smaller degree of clogging of the nozzle of the canister as compared to a formulation prepared by a continuous heating-cooling process. In some embodiments, a foamabie composition produced by a holding process results in less frequent clogging of the nozzle of the canister as compared to a formulation prepared by a continuous heating-cooling process.
• a combination formulation comprising 2% HCO kept at 25 °C for 30 days is non-shakable when prepared by a continuous heating-cooling process and fully shakabie when prepared by a holding process.
• a combination formulation comprising 1 .2% HCO kept at 25 °C for 30 days is moderately shakabie when prepared by a continuous heating-cooling process and fully shakabie when prepared by a holding process.
• formulations kept at 40 °C for 30 days are non-shakable when prepared by a continuous heating-cooling process and moderately shakabie when prepared by a holding process.
• Formulations prepared by a holding process that have the property of superior shakabiiity may comprise Tmh crystals, e.g., nonuniform, larger and more stable crystals that are not present in formulations prepared by a continuous heating- cooling process.
• the stable structures and crystal fingerprint formed by the holding process may be less available to interact with each other or with other components of the formulation and surprisingly improve the fiowability of the formulation, resulting in a fully shakabie formulation.
• preparation by a holding process does not change crystal polymorph, crystal configuration, or crystal lattice of the crystal in the formulation, but changes the formulation shakability.
• a formulation comprising a combination of MCH and ADR with 2% HCO prepared by a continuous heating-cooling process is not shakable after one to six months.
• a formulation comprising MCH and ADR with 1.2% HCO prepared by a continuous heating-cooling process shows a moderate improvement in shakability as compared to a formulation with 2% HCO.
• a formulation containing MCH and ADR with 1 .2% HCO prepared by a holding process e.g. 4 hours at about 54°C
• the flow point of a formulation may be measured by evaluated shear storage modulus [G’) or elastic modulus of a material, a measure of its ability to store deformation energy.
• the foamable composition prepared using the methods disclosed herein has a G’ value between about 50 Pa and about 100 Pa after 1 day at 25 °C. In some embodiments, the foamable composition has a G’ value between about 100 Pa and about 200 Pa after 1 day at 25 °C. In some embodiments, the foamable composition has a G value between about 100 Pa and about 150 Pa after 1 day at 25 °C. In some embodiments, the foamable composition has a G value between about 50 Pa and about 100 Pa after 15 days at 25 °C.
• the foamable composition has a G’ value between about 100 Pa and about 200 Pa after 15 days at 25 °C. in some embodiments, the foamable composition has a G’ value between about 100 Pa and about 150 Pa after 15 days at 25 °C. In some embodiments, the foamable composition has a G’ value between about 200 Pa and about 300 Pa after 15 days at 25 °C. In some embodiments, the foamable composition has a G’ value between about 250 Pa and about 300 Pa after 15 days at 25 °C. In some embodiments, the foamable composition has a G’ value between about 200 Pa and about 250 Pa after 15 days at 25 °C. In some embodiments, the composition has a G’ value between about 200 Pa and about 300 Pa after 30 days at 25 °C.
• the composition has a G’ value between about 300 Pa and about 400 Pa after 30 days at 25 °C. In some embodiments, the composition has a G’ value between about 400 Pa and about 500 Pa after 30 days at 25 °C. In some embodiments, the composition has a G value between about 500 Pa and about 600 Pa after 30 days at 25 °C. in some embodiments, the composition has a G’ value between about 500 Pa and about 550 Pa after 30 days at 25 °C. in some embodiments, the composition has a G’ value between about 550 Pa and about 600 Pa after 30 days at 25 °C. In some embodiments, the composition has a G’ value between about 4000 Pa and about 5000 Pa after 1 day at 40 °C.
• the composition has a G ’ value between about 4000 Pa and about 4500 Pa after 1 day at 40 °C. In some embodiments, the composition has a G value between about 4500 Pa and about 5000 Pa after 1 day at 40 °C. In some embodiments, the composition has a G’ value between about 5000 Pa and about 6000 Pa after 1 day at 40 °C. In some embodiments, the composition has a G’ value between about 6000 Pa and about 7000 Pa after 1 day at 40 °C. In some embodiments, the composition has a G ’ value between about 7000 Pa and about 8000 Pa after 1 day at 40 °C.
• the composition has a G’ value between about 8000 Pa and about 9000 Pa after 1 day at 40 °C. In some embodiments, the composition has a G’ value between about 9000 Pa and about 10000 Pa after 1 day at 40 °C. in some embodiments, the composition has a G’ value between about 6000 Pa and about 7000 Pa after 15 days at 40 °G. In some embodiments, the composition has a G’ value between about 7000 Pa and about 8000 Pa after 15 days at 40 °C. In some embodiments, the composition has a G’ value between about 8000 Pa and about 9000 Pa after 15 days at 40 °C. In some embodiments, the composition has a G’ value between about 9000 Pa and about 10000 Pa after 15 days at 40 °C.
• the composition has a G’ value between about 10000 Pa and about 1 1 000 Pa after 15 days at 40 °C. In some embodiments, the composition has a G’ value between about 1 1000 Pa and about 12000 Pa after 15 days at 40 °C. In some embodiments, the composition has a G’ value between about 12000 Pa and about 13000 Pa after 15 days at 40 °C. In some embodiments, the composition has a G’ value between about 13000 Pa and about 14000 Pa after 15 days at 40 °C. In some embodiments, the composition has a G’ value between about 14000 Pa and about 15000 Pa after 15 days at 40 °C.
• the composition has a G’ value between about 15000 Pa and about 16000 Pa after 15 days at 40 °C. In some embodiments, the composition has a G’ value between about 16000 Pa and about 17000 Pa after 15 days at 40 °C. In some embodiments, the composition has a G’ value between about 17000 Pa and about 18000 Pa after 15 days at 40 °C. In some embodiments, the composition has a G value between about 18000 Pa and about 19000 Pa after 15 days at 40 °C. In some embodiments, the composition has a G’ value between about 5000 Pa and about 6000 Pa after 30 days at 40 °C. In some embodiments, the composition has a G’ value between about 6000 Pa and about 7000 Pa after 30 days at 40 °C.
• the composition has a G’ value between about 7000 Pa and about 8000 Pa after 30 days at 40 °C. In some embodiments, the composition has a G’ value between about 8000 Pa and about 9000 Pa after 30 days at 40 °C. In some embodiments, the composition has a G’ value between about 9000 Pa and about 10000 Pa after 30 days at 40 °C. In some embodiments, the composition has a G’ value between about 10000 Pa and about 1 1 000 Pa after 30 days at 40 °C. In some embodiments, the composition has a G vaiue between about 1 1000 Pa and about 12000 Pa after 30 days at 40 °C.
• the composition has a G’ value between about 12000 Pa and about 13000 Pa after 30 days at 40 °C. In some embodiments, the composition has a G’ value between about 13000 Pa and about 14000 Pa after 30 days at 40 °C. In some embodiments, the composition has a G’ value between about 14000 Pa and about 15000 Pa after 30 days at 40 °C. In some embodiments, the composition has a G’ vaiue between about 15000 Pa and about 16000 Pa after 30 days at 40 °C. in some embodiments, the composition has a G’ value between about 16000 Pa and about 17000 Pa after 30 days at 40 °C. In some embodiments, the composition has a G’ value between about 17000 Pa and about 18000 Pa after 30 days at 40 °C. In some embodiments, the composition has a G value between about 18000 Pa and about 19000 Pa after 30 days at 40 °C.
• Topical therapeutic breakable gel and foamable compositions comprising tetracycline, including those without surfactants, have been described, for example in U.S. Application Serial Nos. 13/499,501 , 13/499,727, 13/499,475, and 13/499,709, U.S. Publication No. 201 1/0281827, WO 1 1 /039637, WO 1 1 /039638, WO 1 1 /138678 and WO 201 1 /064631 , all of which are herein incorporated in their entirety by reference.
• any of the active ingredients, carriers, solvents, surfactants, foam adjuvants, fatty acids, tatty alcohols, polymeric agents, penetration enhancers, preservatives, humectants, moisturizers, and other excipients, as well as the propellants and methods listed therein can be applied herein and are incorporated by reference.
• any of the active ingredients, carriers, solvents, surfactants, foam adjuvants, polymeric agents, penetration enhancers, preservatives, humectants, moisturizers, and other excipients, as well as the propellants and methods listed therein can be applied herein and are incorporated by reference.
• a foamable composition to a target area such as skin of a patient comprising releasing foam, applying it to the area, and collapsing the foam.
• the foam is applied by spreading. In the course of spreading, mechanical shear can cause the foam to collapse.
• the collapsed foam is not washed off. in one or more embodiments it is absorbed onto the area of skin. In one or more embodiments it avoids skin irritation or an ointment sensation.
• a method for reducing the number of acne or rosacea lesions by applying topically an effective amount of a foam or foamable composition to an afflicted area of a patient in need.
• the method involves applying a foam or foamable composition topically to a target surface in need of treatment and breaking the foam over the target site.
• the foam or foamable composition is collapsed and spread by application of a mechanical force, which can be mild or slight such as a simple rub and the active agent is then absorbed.
• the foam or foamable composition is absorbed.
• a foam or foamable composition is absorbed within 240 seconds, or within 200 seconds, or within 180 seconds, or within 150 seconds, within 120 seconds, or within 100 seconds, or within 80 seconds, or within 60 seconds, or within 50 seconds, or within 40 seconds, or within 30 seconds, or within 20 seconds, or within 10 seconds, or within 5 seconds, or within 2 seconds or less.
• the term“absorbed” means that the composition enters onto and into an area of skin, mucosa or eye, often forming a thin coating on the surface.
• the method uses an additional step of pre cleaning and drying the lesions and surrounding area before applying the foam or foamable composition.
• the method uses a sterile applicator or prior to the steps of administering and/or collapsing and/or spreading, the hands of the person spreading are sterilized in order to avoid cross contamination.
• the method comprises an additional step of applying an active agent to the lesions and surrounding area after the foam or foamable composition has been absorbed, wherein the active agent is a hyaluronic acid or a retinoid or benzyl peroxide (“BPO”) or salicylic acid, or an alpha hydroxy acid, or azelaic acid, or nicotinamide, or a keratoiytic agent, or clindamycin, or metronidazole, or doxycycline, or erythromycin, or ivermectin, or brimonidine, or sodium sulfacetamide and sulfur, or tretinoin.
• BPO benzyl peroxide
• the active agent such as, for example, a hyaluronic acid, a retinoid, BPO, salicylic acid, an alpha hydroxy acid, azelaic acid, a nicotinamide, a keratoiytic agent, clindamycin, metronidazole, erythromycin, ivermectin, brimonidine, sodium sulfacetamide and sulfur, tretinoin, or mixtures of two or more thereof, is applied once daily at least 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , or 12 hours after the tetracycline antibiotic formulation has been absorbed.
• the active agent such as, for example, a hyaluronic acid or a retinoid or BPO or salicylic acid, or an alpha hydroxy acid, or azelaic acid, or nicotinamide, or a keratoiytic, or clindamycin, or metronidazole, or erythromycin, or ivermectin, or brimonidine, or sodium sulfacetamide and sulfur, or tretinoin, is applied after the third day.
• a hyaluronic acid or a retinoid or BPO or salicylic acid or an alpha hydroxy acid, or azelaic acid, or nicotinamide, or a keratoiytic, or clindamycin, or metronidazole, or erythromycin, or ivermectin, or brimonidine, or sodium sulfacetamide and sulfur, or tretinoin
• the active agent such as, for example, a hyaluronic acid or a retinoid or BPO or salicylic acid, or an alpha hydroxy acid, or azelaic acid, or nicotinamide, or a keratoiytic agent, or clindamycin, or metronidazole, or erythromycin, or ivermectin, or brimonidine, or sodium sulfacetamide and sulfur, or tretinoin, is applied during the maintenance stage.
• a hyaluronic acid or a retinoid or BPO or salicylic acid or an alpha hydroxy acid, or azelaic acid, or nicotinamide, or a keratoiytic agent, or clindamycin, or metronidazole, or erythromycin, or ivermectin, or brimonidine, or sodium sulfacetamide and sulfur, or tretinoin
• the active agent such as, for example, a hyaluronic acid or a retinoid or BPO or salicylic acid, or an alpha hydroxy acid, or azelaic acid, or nicotinamide, or a keratoiytic agent, or clindamycin, or
• metronidazole or erythromycin, or ivermectin, or brimonidine, or sodium
• sulfacetamide and sulfur, or tretinoin is replaced with or supplemented by a steroid.
• the active agent such as, for example, a hyaluronic acid or a retinoid or BPO or salicylic acid, or an alpha hydroxy acid, or azelaic acid, or nicotinamide, or a keratoiytic agent or steroid, or clindamycin, or metronidazole, or erythromycin, or ivermectin, or brimonidine, or sodium
• the antibiotic which is in addition to one or more tetracycline antibiotics, is selected from the group consisting of mupirocin, fusidic acid, a penicillin or penicillin derivative, augmentin, an antistaphyiococcal penicillin, amoxicillin/clavulanate, a cephalosporin, cephalexin, a macroiide, erythromycin, clindamycin, trimethoprim-sulfamethoxazole penicillin, rumblemulin, and mixtures of any two or more thereof.
• the antibiotic is applied topically.
• the antibiotic is applied orally, by injection, or by infusion. In some embodiments, more than one antibiotic is applied. For example, an antibiotic is applied topically and another is given orally. This scenario can be appropriate in some instances, e.g., where there is systemic as well as topical bacterial infection.
• the regimen comprises administering topically the foams or foamable compositions or compositions described herein once, twice, three times, four times, five times, or six times a day to a surface having acne. In some embodiments, the regimen comprises administering topically the foam, foamable composition, or compositions described herein once every day, every two days, every three days, every four days, every five days, every six days, or every seven days to a surface having acne. In some embodiments, the regimen comprises administering topically the foam, foamable composition, or compositions described herein intermittently, or as needed, to a surface having acne.
• the regimen comprises administering the foam, foamable composition, or compositions described herein to a surface having acne, for at least one week, at least two weeks, at least three weeks, at least four weeks, at least five weeks, at least six weeks, at least seven weeks, at least eight weeks, at least three months, at least four months, at least five months, at least six months, at least seven months, at least eight months, at least night months, at least ten months, at least eleven months, at least one year, at least two years, at least three years, at least four years at least five years, at least six years, at least seven years, at least eight years, at least nine years or at least ten years.
• foam, foamable composition, or compositions e.g., foamable compositions and or compositions comprising tetracycline-based antibiotics disclosed herein, can be administered topically to treat skin disorders, e.g., acne congiobata, acne vulgaris, rosacea.
• skin disorders e.g., acne congiobata, acne vulgaris, rosacea.
• the terms“treat,” "treatment,” and other related forms of the term comprise a step of administering, e.g., topically, an effective dose, or effective multiple doses, of a foamab!e composition and /or composition comprising a tetracycline-based antibiotic as disclosed herein to an animal (including a human being) in need thereof if the dose is administered prior to onset of symptoms of a disorder/disease, the administration is prophylactic. If the dose is administered after the development of a disorder/disease, the administration is therapeutic.
• an effective dose is a dose that partially or fully alleviates (i.e., eliminates or reduces) at least one symptom associated with the disorder/disease state being treated, that slows or prevents progression to a disorder/disease state, that slows or prevents progression of a disorder/disease state, that diminishes the extent of disease, that results in remission (partial or total) of disease, and/or that prolongs survival.
• diseases states contemplated for treatment are set out herein.
• acne is a general term that describes a common skin disorder, which afflicts many people. The prevalence of adult acne is about 3% in men and between about 1 1% and 12% in women. Moderate to severe acne is observed in 14% of acne patients. There are various types of acne recognized in the field, including, for example: acne vulgaris, acne conglobate, acne fulminans, and nodular
• Acne vulgaris (cystic acne or simply acne) is generally characterized by areas of skin with seborrhea (scaly red skin), comedones
• Acne can be inflammatory acne and or non-inflammafory acne.
• Acne vulgaris may affect the face, the upper part of the chest, and the back. Severe acne vulgaris is inflammatory, but acne vulgaris can also manifest in non-inflammatory forms.
• Acne congiobata is a severe form of acne, and may involve many inflamed nodules that are connected under the skin to other nodules. Acne congiobata often affects the neck, chest, arms, and buttocks.
• patients treated with the compositions disclosed herein are first diagnosed with acne.
• patients may be diagnosed according to Eichenfieid et al, using a differential diagnosis for pediatric acne which depends on, inter alia, age group, pubertal status, and form of presentation.
• differential diagnosis may turn on, inter alia, detection of one or more of demodex folliculitis, gram negative folliculitis, keratosis pilaris, malassezia (pityrosporum) folliculitis, popular sarcoidosis, perioral dermatitis, pseudofolliculitis barbae, and tinea faciei.
• acne may present as acne venenata or pomade acne (from the use of topical oil-based products), and diagnosis may turn on, inter alia, detection of one or more of angiofibromas or adenoma sebaceum, corticosteroid-induced acne, fiat warts, keratosis pilaris, milia, moliuscum
• Mid-childhood acne (1-7 y of age) may warrant an endocrinologic workup for causes of hyperandrogen ism, and may be associated with adrenal tumors, congenital adrenal hyperplasia, cusbing syndrome, gonadal tumors, ovarian tumors, PCOS, premature adrenarche, or true precocious puberty.
• the physical examination may include type and distribution of acne lesions, height, weight, growth curve, and possible blood pressure abnormalities.
• Preadoiescent acne may be characterized by a predominance of comedones on the forehead and central face (the so-called“T-zone”) with relatively few inflammatory lesions. Early presen tation may include comedones of the ear. Mid-childhood acne typically presents primarily on the face with a mixture of comedones and inflammatory lesions. See, Eichenfield et al., Pediatrics. (2013); 131 (supp! 3): S183-S186.
• Zaengiein et al describes other acne diagnostic tools that may be used, e.g , in adults treated with a composition disclosed herein, taking into account various factors, such as type of acne, severity of acne, number of acne lesions, anatomic location/extent of acne, quality of life and other psychosocial metrics, and scarring.
• Scientific measures such as ultraviolet-induced red fluorescence, casual sebum level, skin capacitance imaging, skin surface pH, and transepidermai water loss may help to more objectively classify and rate acne. See, Zaengiein J AM ACAD DERMATOL (MAY 2016), 949-950.
• a foamab!e combination product (3% minocycline / 0.3% adapa!ene as active agents) for treating acne in a further embodiment, the acne is moderate-to -severe acne vulgaris in one or more embodiments the combination product is more effective than the vehicle without the active agents in one or more embodiments the combination product is more effective than the product with minocycline alone in one or more embodiments the combination product is more effective than the product with adapaiene alone. In one or more embodiments the product is delivered as a foam.
• a method for treating acne conglobata or acne vulgaris in a patient in need thereof comprising: administering to the patient a composition and /or foamable composition or foam as described herein, wherein the foamable composition or foam comprises a
• compositions and/or foamable compositions or foams comprising 3% minocycline and 0.3% adapaiene are administered topically once daily to the full face and other acne-affected areas of the body for 12 weeks in some embodiments, compositions and/or foamable
• compositions or foams comprising 3% minocycline are administered topically once daily to the full face and other acne-affected areas of the body for 12 weeks.
• compositions and/or foamable compositions or foams comprising 0.3% adapaiene are administered topically once daily to the full face and other acne- affected areas of the body for 12 weeks.
• the compositions and /or foamable compositions or foams are applied daily at a fixed time, e.g., about 1 hour before bedtime or about 2 hours before bedtime, to the full face and other acne-affected areas of the body.
• the daily dose is no more than 150 mg of minocycline, e.g., about 140 mg, about 130 mg, about 120 mg, or about 1 10 g. In some embodiments, the daily dose is no more than 15 mg adapaiene, e.g., about 14 mg, about 13 mg, about 12 mg, about 1 1 mg, about 10 mg, or about 9 mg. In some embodiments, the daily dose is about 106 mg of minocycline. In some embodiments, the daily dose is about 10.6 mg adapaiene. In some embodiments, the cumulative maximal dose is no more than 12 g of minocycline, e.g., 1 1 g, 10 g, 9 g, 8 g, or 7 g.
• the cumulative maximal dose is no more than 8.9 g of minocycline. In some embodiments, the cumulative maximal dose is no more than 1.2 g of adapaiene, e.g., 1.1 g, 1 .0 g, 0 9 g, 0.8 g, or 0.7 g. In some embodiments, the cumulative maximal dose is no more than 0.89 g of adapaiene.
• the patient is 8-100 years old. In some other embodiments, the patient is at least 12 years of age. In some embodiments, the patient is a male patient, e.g., one who is 8-100 years old, or at least 12 years old.
• the patient is a female patient, e.g., one who is 8-100 years old, or at least 12 years old.
• the patient has been or concurrently is diagnosed with acne conglobata or acne vulgaris prior to treatment, e.g., by a clinical examination in some embodiments, acne conglobata or acne vulgaris is diagnosed by a clinical evaluation of symptoms, e.g. Investigator’s Global Assessment (IGA) of Acne Severity in some embodiments, acne conglobata or acne vulgaris is defined as any disorder of the skin whose initial pathology is microscopic microcomedo. In some embodiments, microcomedo evolve into visible open comedones
• blackheads or closed comedones (“whiteheads”) in some embodiments, patients are diagnosed with acne conglobata or acne vulgaris based on a physical examination.
• the severity of the disease may be determined by lesion counting in some embodiments, microcomedo evolve into inflammatory papules, pustules, and nodules.
• the severity of acne conglobata or acne vulgaris is determined by lesion counting in some embodiments, the severity of acne conglobata or acne vulgaris is determined by counting the number of open comedones on the affected area. In some embodiments, the severity of acne conglobata or acne vulgaris is determined by counting the number of closed comedones on the affected area.
• the severity of acne conglobata or acne vulgaris is determined by counting the number of papules in the affected area in some embodiments, the severity of acne conglobata or acne vulgaris is determined by counting the number of pustules in the affected area. In some embodiments, the severity of acne conglobata or acne vulgaris is determined by counting the number of nodules in the affected area. In some embodiments, the severity of acne conglobata or acne vulgaris is determined by counting the number of papules and pustules in the affected area in some embodiments, the severity of acne conglobata or acne vulgaris is determined by counting the number of papules, pustules, and nodules in the affected area.
• the patient has 10-100 inflammatory lesions (papules and/or pustules) on the face in some embodiments, there are 20-50 inflammatory lesions (papules and/or pustules) on the face. In some embodiments, there are 0-200 non-infiammatory lesions (open and closed comedones) on the face. In some embodiments, there are 20-150 non inflammatory lesions (open and closed comedones) on the face. In some
• the Investigator’s Global Assessment (IGA) of Acne Seventy is a classification scheme for the severity of primary acne vulgaris on a scale of 0 to 4. Pochi et a! , J. Am. Acad. Dermatol., (1991) 24:495-500. A score of zero indicates that the acne is‘clear’ and residual hyperpigmentation and erythema may be present A score of one indicates that the acne is“almost clear” with a few scattered comedones and a few small papules.
• a score of two indicates that the acne is“mild’ with some comedones and some papules and pustules, and less than half the face is involved
• a score of three indicates that the acne is‘moderate’ with more than half the face affected, many comedones, papules, and pustules, a possibly one nodule present.
• a score of four indicates that the acne is‘severe’ with involvement of the entire face, numerous papules and pustules, and a few nodules and cysts.
• the patient has a IGA score of at least 2, e.g., 2, 3, or 4 in some embodiments, a patient treated with a composition disclosed herein has an IGA score of 3 or 4.
• the patient has no more than one active nodule on the face. In some embodiments, the patient has no more than two active nodules on the face.
• the patient is diagnosed with acne vulgaris, with at least one or more of (1 ) 20 to 50 inflammatory lesions (papules and/or pustules) on the face; (2) 25 to 100 non-infiammatory lesions (open and closed comedones) on the face; and (3) IGA score of moderate (3) to severe (4).
• the pre-screening of patients amenable to treatment is also contemplated, e.g., according to the methods of identifying acne vulgaris patients disclosed herein, as well as the administration of treatment to patients identified according to criteria disclosed herein.
• a female patient does not have a positive urine pregnancy test in some embodiments, the patient uses an effective method of contraception while undergoing treatment.
• the patient using a hormonal contraceptive uses the same type and strength of contraceptive over the 3 months prior to the start of treatment.
• the patient does not use any other acne medication concurrently with the treatment described herein.
• the patient does not use a medicated cleanser during the treatment described herein.
• the patient does not have excessive sun exposure during the treatment described herein.
• the patient does not use a fanning booth during the treatment described herein.
• a patient who is female Is not pregnant or lactating in some embodiments, the patient does not have acne conglobata, acne fulminans, secondary acne (chloracne, drug-induced acne), or any dermatological condition of the face that could interfere with the clinical evaluations.
• the patient does not have facial hair, e.g., beard or mustache, that could interfere with clinical evaluations.
• the patient does not have a sunburn on the face.
• the patient does not have any sever systemic disease, e.g., lupus, multiple schierosis, that could interfere with clinical evaluations.
• the patient does not have a documented history of an allergy to tetracycline-class antibiotics, or to any components in the pharmaceutical compositions described herein.
• the patient does not have a documented history ot
• the patient does not have a documented history of hepatitis or clinically significant liver damage or renal impairment. In some embodiments, the patient does not have a documented history of a known or suspected premaiignant or malignant disease excluding successfully treafed skin cancers.
• the patient has not used medicated facial cleansers within one week prior to the start of treatment in some embodiments, the patient has not used a topical acne treatment on the face within one week prior to the start of treatment in some embodiments, the patient has not used topical retinoids on the face within four weeks prior to the start of treatment. In some embodiments, the patient has not used topical anti-inflammatories and/or
• corticosteroids on the face within four weeks prior to the start of treatment has not used topical corticosteroids on body areas other than the face for more than 15 consecutive days and on more than 10% of the body surface area within four weeks prior to the start of treatment.
• the patient has not used topical corticosteroids on body folds, such as axillary and inguinal regions, for more than 15 consecutive days within four weeks prior to the start of treatment.
• the patient has not used systemic antibiotics within four weeks prior to the start of treatment in some embodiments, the patient has not used systemic acne treatments within four weeks prior to the start of treatment.
• the patient has not used systemic retinoids within twelve weeks prior to the start of treatment in some embodiments, the patient has not used systemic corticosteroids within twelve weeks prior to the start of treatment in some embodiments, the patient has not used a sauna within two weeks prior to the start of treatment. In some embodiments, the patient has not undergone epilation of the face within two weeks prior to the start of treatment. In some embodiments, the patient does not have folliculitis on the face in some
• the patient does not have documented drug addiction or alcohol abuse within two years prior to the start of treatment, with heavy drinking levels defined by The Substance Abuse and Mental Health Services Administration (SAMHSA) as drinking 5 or more alcoholic drinks on the same occasion on each of 5 or more days in the past 30 days.
• SAMHSA Substance Abuse and Mental Health Services Administration
• the patient does not have a documented history of depression that is not adequately controlled by medication at the time of treatment.
• treatment efficacy is assessed by comparing the patient to a control, e.g., a subject who does not have acne, historic data, and/or taking into account the developmental history of acne in some embodiments, treatment efficacy is assessed by comparing the patient condition before and after receipt of treatment to the known natural history of acne. In some embodiments, treatment efficacy is assessed by comparing the patient's current condition with the patient's condition prior to treatment (baseline).
• treatment efficacy is assessed by comparing the condition of one group of patients at different time points after receiving a composition comprising one active agent with that of a second group of patients receiving a composition comprising a second active agent. In some embodiments, treatment efficacy is assessed by comparing the condition of one group of patients at different time points after receiving composition comprising one active agent to that of a second group of patients after receiving a composition comprising a combination of active agents in some embodiments, treatment efficacy is assessed by comparing the condition of one group of patients’ after receiving the composition comprising one or more active agent with patients’ condition receiving the vehicle at different time points compared to baseline. For example, treatment efficacy for a patient with acne vulgaris may be assessed by the following
• treatment may be considered efficacious if symptoms stabilize and/or do not worsen, e.g., no further increase in the number of lesions or no further progression of symptoms if observed in some embodiments, treatment may be considered efficacious if an improvement in symptoms is observed, e.g. decrease in the number of lesions or improvement in IGA score. In some embodiments, treatment may be considered efficacious if IGA Treatment Success, e.g where success is defined as an IGA score of 0 or 1 , and at least a 2- grade improvement (decrease) from Baseline.
• treatment efficacy is assessed by the absolute change in inflammatory lesion count after the start of treatment, e.g., 4 weeks, 8 weeks, or 12 weeks after the start of treatment, compared to the baseline before treatment.
• treatment efficacy is assessed by the absolute change in inflammatory lesion count 12 weeks after the start of treatment, compared to the baseline before treatment in some embodiments, treatment efficacy is assessed by the absolute change in non-inflammatory lesion count after the start of treatment, e.g., 4 weeks, 8 weeks, or 12 weeks after the start of treatment, compared to the baseline before treatment in some embodiments, treatment efficacy is assessed by the absolute change in non-inflammatory lesion count 12 weeks after the start of treatment, compared to the baseline before treatment.
• treatment efficacy is assessed by a 2-grade decrease on the IGA scale after the start of treatment, e.g., 4 weeks, 8 weeks, or 12 weeks after, compared to the baseline before treatment in some embodiments, treatment efficacy is assessed by a 2-grade decrease on the IGA scale 12 weeks after the start of treatment, compared to the baseline before treatment. In some embodiments, treatment efficacy is assessed by a score of 0 or 1 on the IGA scale after the start of treatment, e.g., 4 weeks, 8 weeks, or 12 weeks after, compared to the baseline before treatment in some embodiments, treatment efficacy is assessed by a score of 0 or 1 on the IGA scale 12 weeks after the start of treatment, compared to the baseline before treatment.
• treatment efficacy is assessed by a score of 0 or 1 on the IGA scale and a 2-grade decrease on the IGA scale 12 weeks after the start of treatment, compared to the baseline before treatment.
• treatment efficacy is assessed by a score of 0 or 1 on the IGA scale and a 2-grade decrease on the IGA scale after the start of treatment, e.g., 4 weeks,
• treatment satisfaction is assessed by subject satisfaction
• treatment satisfaction is assessed by subject satisfaction questionnaire 12 wee ks after the start of treatment, compared to the baseline before treatment.
• subject satisfaction is assessed by comparing the percent in condition improvement in one group of patients’ after receiving the composition comprising one or more active agent or receiving the vehicle at different time points compared to baseline.
• safety is assessed using measures, including physical examinations, the monitoring of vital signs, TEAEs (volunteered, observed, and elicited by general questioning in a non-suggestive manner), and local skin tolerability assessments.
• Tolerability to a drug or treatment can be measured by the appearance of adverse side effects or toxicity. In some embodiments, tolerability to the treatment is assessed.
• local skin tolerability (face only) is assessed based on subject-rated itching and stinging/burning, and assessments of dryness, scaling, erythema and hyperpigmentation in some embodiments, treatment- emergent adverse events (TEAE) are assessed after the start of treatment, e.g , 4 weeks, 8 weeks, 12 weeks or 16 weeks after treatment in some embodiments, TEAE are assessed by patient questionnaires, observations, physical examinations, vital signs and local skin tolerability assessments, which may include itching, stinging, burning, dryness, scaling, erythema, and hyperpigmentation. In some embodiments, TEAE or local skin tolerability are assessed by the same evaluator throughout the study whenever possible.
• a method of treating a subject for acne comprising diagnosing a subject having acne as at risk for tissue damage, wherein tissue damage comprises scarring, postinflammatory hyperpigmentation and/or residual erythema.
• a method of treating a subject for acne with combination product e.g. a composition comprising a combination of minocycline 3% and adapalene 0.3%, e.g., one prepared with or without a holding step
• a method of treating a subject for acne with combination product which is numerically superior to vehicle with respect to absolute change from baseline in non-inflammatory lesion counts in one or more embodiments these findings are supported by sensitivity analyses and results of secondary efficacy analyses.
• a method of treating a subject for acne with combination product wherein secondary efficacy analyses compare the combination product with the two individual active agents, minocycline 3% or adapalene 0.3%.
• a method of treating a subject for acne with combination product is statistically superior to adapalene 0.3% in absolute change from baseline in inflammatory and non- inflammatory lesion counts at week 12.
• a method of treating a subject for acne wherein treatment with combination product is statistically superior to minocycline 3% in absolute change from baseline in non inflammatory lesion counts at week 12.
• a method of treating a subject for acne wherein treatment with combination product is numerically superior to minocycline 3% in absolute change from baseline in inflammatory lesion counts at week 12. In one or more embodiments there is provided a method of treating a subject for acne wherein treatment with combination product is statistically superior for IGA treatment success, to adapalene 0.3% at week 12. In one or more embodiments there is provided a method of treating a subject for acne, wherein treatment with combination product is numerically superior for IGA treatment success, to minocycline 3% at week 12.
• the combination of minocycline and adapalene in the vehicle is effective against acne and all three components can contribute to successful treatment that is advantageous in treating both inflammatory and non-inflammatory lesions and can provide subjects with new and better treatment options.
• a method of treating a subject for acne wherein treatment with a combination product exhibits a favorable safety profile, with the majority of TEAEs being characterized as mild or moderate in one or more embodiments, there is provided a method of treating a subject for acne, wherein the primary treatment-related TEAEs include dry skin, rash, acne, and eye irritation. In one or more embodiments, there is provided a method of treating a subject for acne with a combination product, wherein the potential forTEAEs is reduced.
• a method of treating a subject for acne wherein treatment with a combination product is effective and safe with administration of other concomitant medicines (e.g., sex hormones and modulators of the genital system, other gynecologicals, psychoanaleptics, vitamins, analgesics, anti- inflammatory and antirheumatic products, and/or antihistamines for systemic use, emollients and protectives) with no apparent drug interactions.
• concomitant medicines e.g., sex hormones and modulators of the genital system, other gynecologicals, psychoanaleptics, vitamins, analgesics, anti- inflammatory and antirheumatic products, and/or antihistamines for systemic use, emollients and protectives
• the most commonly used class of concomitant medications is sex hormones and modulators of the genital system.
• a method of treating a subject for acne wherein the number of subjects reporting concomitant medications is highest in the adapalene 0.3% arm.
• a method of treating a subject for acne wherein fhe most commonly used class of concomitant medications in the adapalene 0.3% arm is sex hormones and modulators of the genital system.
• Rosacea is a chronic acneiform disorder affecting skin and potentially the eye. It is a syndrome of undetermined etiology characterized by both vascular and papu!opustu!ar components involving the face and occasionally the neck, scalp, ears and upper trunk. Clinical findings include mid facia! erythema, telangiectasis, papules and pustules, and sebaceous gland hypertrophy. Rosacea is characterized by episodic flushing of affected areas, which can be triggered by various factors, such as consumption of alcohol, hot drinks, spicy foods or physical exercise.
• Facial rosacea is classified/graded in multiple clinical forms: (1 ) eryfhematote!angiectatic rosacea which is characterized by (semi-) permanent erythema and/or flushing; (2) papu!opustuiar rosacea, characterized by presence of inflammatory lesions such as papules and pustules; (3) phy atous rosacea characterized by circumscribed permanent swelling/thickening of skin areas, typically the nose; and (4) ocular rosacea characterized by the appearance of redness in eyes and eyelids due to teiangiectasias and inflammation, feeling of dryness, irritation, or gritty, foreign body sensations, itching, burning, stinging, and sensitivity to light, eyes being susceptible to infection, or blurry vision.
• a patient treated with a composition disclosed herein is first diagnosed with rosacea.
• the diagnosis of rosacea may be made clinically, e.g., based on visible assessment and patient history, after other causes of facial erythema and/or papulopustu!ar skin lesions have been excluded, including contact dermatitis, seborrheic dermatitis, photodamage, acne vulgaris, cutaneous lupus, and carcinoid syndrome.
• rosacea may include, inter alia, fixed centrofacial erythema in a characteristic pattern that may periodically intensify, phymatous changes, flushing, papules and pustules, telangiectasia, and/or ocular manifestations comprising lid margin telangiectasia, interpalpebrai conjunctiva! injection, spade-shaped infiltrates in the cornea and scieritis and sderokeratitis.
• Other diagnostic features may include burning or stinging sensations on skin (e.g., centrofacial skin), edema, dryness and ocular manifestations. See, Thiboutot et al., J. Am Acad Dermatol. (2020) 82: 1501 -1510.
• Rosacea occurs most commonly in adult life, between the ages of 30 and 60 years. It is very common in skin types l-li (according Fitzpatrick) and more common in Caucasians, with a prevalence of up to 5% in the U.S. and in Europe. It is estimated that from 10 to 20 million Americans have the condition.
• a method for treating rosacea in a patient in need thereof.
• the method comprises: administering to the patient a composition and /or foamable composition or foam as described herein, wherein the foamable composition or foam comprises a tetracycline antibiotic.
• compositions and/or foamable compositions or foams comprising about 1 to about 5%, e.g., about 3% minocycline are administered topically once daily to the full face and other rosacea-affected areas of the body for 12 weeks in some embodiments, compositions and/or foamable compositions or foams comprising 3% minocycline are administered topically once daily for 12 weeks in some embodiments, the compositions and /or foamable compositions or foams are applied daily at a fixed time, e.g., about 1 hour before bedtime or about 2 hours before bedtime.
• the daily dose is no more than 150 mg of minocycline, e.g., about 140 mg, about 130 mg, about 120 mg, or about 1 10 mg. In some embodiments, the daily dose is about 106 mg of minocycline in some embodiments, the cumulative maximal dose is no more than 12 g of minocycline, e.g., 1 1 g, 10 g, 9 g, 8 g, or 7 g. In some embodiments, the cumulative maximal dose is no more than 8.9 g of minocycline.
• a method for treating rosacea in a patient in need thereof comprising: administering to the patient a foamable composition or foam as described herein, wherein the foamable composition or foam is comprises a tetracycline-based antibiotic.
• foamable compositions or foams comprising 3% minocycline and 0.3% adapalene are administered topically once daily to the full face and other affected areas of the body for 12 weeks.
• foamable compositions or foams comprising 3% minocycline are administered topically once daily to the full face and other affected areas of the body for 12 weeks in some embodiments, foamable compositions or foams comprising 0.3% adapalene are administered topically once daily to the full face and other affected areas of the body for 12 weeks in some embodiments, the foamable compositions or foams are applied daily at a fixed time, e.g., about 1 hour before bedtime or about 2 hours before bedtime, to the full face and other affected areas of the body.
• a method of treating a subject for rosacea comprising diagnosing a subject having rosacea as at risk for tissue damage, wherein the tissue damage comprises circumscribed permanent swelling/thickening of skin areas, typically the nose, and administering a composition disclosed herein.
• a method of treating a subject for rosacea comprising diagnosing a subject having rosacea as at risk of developing ocular damage, wherein ocular damage comprises dryness, burning and stinging, light sensitivity, blurred vision, foreign body sensation, lid margin and conjunctival telangiectases, plugging of the meibomian glands, chalazia, chalazion affecting the eyelid, corneal inflammation and scarring and/or corneal perforation or loss of visual acuity, and administering a composition disclosed herein.
• a method of treating a subject for rosacea comprising diagnosing a subject having rosacea as at increased risk of a growing number of systemic disorders comprising cardiovascular, gastrointestinal, neurological, autoimmune disease and/or cancer, and administering a composition disclosed herein.
• a method of treating a subject for acne or rosacea comprising diagnosing a subject having acne rosacea as at risk of mental or social damage, wherein said damage comprising social, psychological and/or emotional symptoms, and administering a composition disclosed herein.
• the psychological and emotional symptoms comprise depression and/or anxiety in one or more embodiments the social symptoms interfere with social or occupational interactions.
• a topical skin disorder in a subject comprising topically administering to a subject in need thereof a therapeutically effective amount of a formulation provided herein.
• the disorder includes at least one etiological factor selected from the group consisting of an infection, an inflammation, oxidative stress, neurodegeneration, and apoptosis.
• the disorder is one or more of dermatological pain, dermatological inflammation, dermatitis, bacterial skin infections, fungal skin infections, viral skin infections, impetigo, pruritis, cellulitis, folliculitis, rashes, trauma or injury to the skin, post-operative or post-surgical skin conditions, eczemas, actinic keratosis, psoriasis, dermatitis, contact dermatitis, atopic dermatitis, or skin scarring.
• compositions and/or foamable compositions or foams comprising minocycline (e.g., about 3% minocycline) and adapalene (e.g., about 0.3% adapalene) are administered topically once daily (or some other appropriate dosing schedule) to the disorder- affected area(s) of the body as appropriate for about 1 to 12 weeks.
• compositions and foamable compositions are disclosed herein, and in Table 1 . Equivalent, and in some cases, similar materials from other manufacturers can also be used.
• Foam quality can be graded as follows:
• Grade E excellent: very rich and creamy in appearance, does not show any bubble structure or shows a very fine (small) bubble structure; does not rapidly become dull: upon spreading on the skin, the foam retains the creaminess property and does not appear watery.
• Grade G (good): rich and creamy in appearance, very small bubble size, "dulls” more rapidly than an excellent foam, retains creaminess upon spreading on the skin, and does not become watery.
• Grade FG (fairly good): a moderate amount of creaminess noticeable, bubble structure is noticeable: upon spreading on the skin the product dulls rapidly and becomes somewhat lower in apparent viscosity.
• Grade F very little creaminess noticeable, larger bubble structure than a "fairly good” foam; upon spreading on the skin it becomes thin in appearance and watery.
• Grade P no creaminess noticeable, large bubble structure, and when spread on the skin it becomes very thin and watery in appearance.
• Grade VP very poor: dry foam, large very dull bubbles, difficult to spread on the skin.
• Collapse Time which is a measure of thermal stability, is measured by dispensing a given quantity of foam and photographing sequentially its appearance over time while incubating at 36 e C.
• the collapse time is defined as the time when the foam height reaches 50% of its initial height. However, if the foam takes longer than a threshold time, e.g., 180 seconds (s), to collapse to 50% of its initial height, then the collapse time may be recorded as >180 s.
• a threshold time e.g. 180 seconds (s)
• one foam may remain at 100% of its initial height for three minutes
• a second foam may collapse to 90% of its initial height after three minutes
• a third foam may collapse to 70% of its initial height after three minutes
• a fourth foam may collapse to 51% of its initial height after three minutes.
• the collapse time is recorded as >180 seconds.
• a foam is more easily applied to a target area if the majority of the foam remains intact for a reasonable period of time at 36 e G e.g., for more than 100 seconds, or more than 180 seconds. If, for example, the foam is reduced to 50% of its original height after 100 s, it would be recorded as having a collapse time of 100 s.
• the rate of drainage can be measured in a similar way to the collapse time.
• the foam In the collapse time method, the foam is observed and filmed for a set period of time, e.g., 180 seconds. The height of the foam is measured against a marked ruler and any changes are recorded. The foam quality, as described above, is also observed throughout and any change in quality is noted. If a reduction in quality is observed, e.g., from Good to Fairly Good or from Excellent to Good, then significant drainage is considered to have occurred and the approximate time point when this change has been noted is said to be the drainage time.
• a picture of the foam is taken at time intervals: 10, 30, 60, 90, 120, 150 and 180 seconds. At each time point the foam quality is assessed visually. The time taken by the foam to get to FG quality is recorded.
• Rheology analysis on placebo samples is made using a DHR3 rheometer (which provides similar measurements to the DHR2 rheometer used with API samples) from TA instruments.
• Rheology analysis on active samples is made using a DHR2 rheometer from TA instruments.
• the geometry used is a 40 mm parallel steel plate using a 1000 pm gap with temperature controlled by a Peltier bottom plate. Rotational measurements are made to obtain the viscosity at 36 s 1 . Oscillatory measurements are made to obtain the viscoelastic parameters. All measurements are made within the linear viscoelastic region.
• the elastic modulus G’ is obtained from the frequency sweep where the values are independent from the frequency.
• the flow point is obtained after a temperature sweep from 25 °C to 90 °C is performed.
• the flow point is the temperature at which G” becomes higher than G’ and corresponds to the temperature at which the system starts flowing.
• PFF pre-foam formulation
• a probe (Aluminum cylinder probe;
• the test material (dimensions: 25.5 mm, diameter; 6.4 mm height; Agentek ⁇ ) is inserted into the test material.
• the resistance of the material to compression is measured by a calibrated load cell and reported in units of grams on the texture analyzer instrument display. Preferably at least three repeat tests are conducted.
• the textural characteristics of a dispensed foam can affect the degree of dermal penetration, efficacy, spreadability and acceptability to the user A lower resistance to compression indicates a softer foam. Note: the foam sample is dispensed into an aluminum sample holder
• Adhesion or adhesiveness is measured.
• Adhesiveness is defined as the force (g) needed to overcome attraction between two surfaces which are in contact. Measurements are made using the LFRA Brookfield Texture Analyzer.
• the two surfaces can be sections of artificial, actual tissue, or skin, and measure about 2 X 2 cm. During the measurement, one surface is positioned in the center of a Petri dish and the other surface is attached to the base of texture analyzer probe A sample of pre-foam or foamable composition is spread uniformly on the surface that is on the Petri dish. The probe is moved down and up, first bringing the two sections into contact, then separating them.
• the Texture Analyzer measures the force for separating the surfaces, wherein the adhesive force is expressed as a negative force with the force to bring the two sections in contact as a positive force
• Polarized optical microscopy Photomicrographs of placebo samples are taken throughout a heating cycle from 25 °C to 80 °C.
• the microscope used is an Olympus BX51 , the camera is a Digital Hitachi Camera and the heating stage is a Linkam stage.
• Photomicrographs of active samples are taken using ZEISS
• Axioscope 7 equipped with Axiocam 305 digital camera and ZEN software. Heating was performed with Linkam hotstage with Linkpad touchscreen.
• SAXSLAB GANESHA 3G0-XL (Skovlunde, Denmark), is used to measure the small angle x-ray scattering.
• Cu Kcs radiation is generated by a Genix 3D Cu-source (operated at 47 mV and 0.55 mA) with integrated monochromator, 3 pinholes for coilimation and a two-dimensional Pilatus 300K detector. The distance between the sample and detector is measured at two different configurations: 350 mm and 50 m .
• the q range is between 0.012 to 0.67 A 1 and between 0.05 to 1 .8 A -1 respectively.
• Angular scans are obtained from 3° fo 35° using a step size of 0.016° and a scan speed of 0.046 s.
• Formulations prepared by a continuous heating-cooling process or a holding process are heated to a temperature of 50 °G. At this temperature most crystals observed correspond to hydrogenated castor oil and display a spheruiite structure (for a continuous heating-cooling process) or a nonuniform structure (for a holding process). Analysis of these different structures is performed by light microscopy (Olympus BX51 , Camera: Digital Hitachi and heating stage: Linkam stage).
• PFF pre-foam formulations
• samples are loaded onto a shaker and shaken with increasing time (s) and frequencies (Hz) through six different levels until the samples reach optimal shakability (i.e., when one can hear and feel the material movement inside the canister as compared to the control sample).
• the testing level at which each sample reaches comparable shakability with the control sample is recorded.
• a result of testing levels 0-3 indicates "shakabie (S)”
• a result of testing levels 4-6 indicates “moderately shakabie (M)”. If the sample completes testing level 6 and is still not shakabie it should be assigned a result of testing level“6+” and indicates a "Non -shakabie (N)”.
• shakability represents the degree to which the user is able to feel and/or hear the presence of the liquid contents when the filled pressurized canister is
• the mixtures of sebum with the test formulations are prepared as follows: the formulation of interest is weighed out and placed together with sebum into a glass test tube at ambient temperature, mixed manually with a stainless-steel spatula and then vortexed for 1 minute.
• the foam is dispensed from the pressurized canister into a beaker and is manually collapsed by mixing with a glass rod. Then, the collapsed toam is mixed with sebum in the same way as described above.
• the resulting mixtures are tested by differential scanning calorimetry (DSC). Signal min x measurements are taken for each endotherm peak and represent the melting temperature ot the evaluated sample.
• the DSC thermogram of the model sebum used in this study exhibits main broad melting endotherm with the signal min x at about 37 °C and several other minor endotberms at lower temperatures it is the endotherm located in the temperature range close to the skin temperature, which is the focus for evaluation of follicular delivery.
• the differential scanning calorimeter DSC250 or DSC2500, TA instruments, New Castle, DE is used for DSC experiments.
• the sample is placed into a T-zero aluminum pan and crimped with a T-zero hermetic lid.
• the samples are cooled to 0 °C at 5 °C/min, held at 0 °C for 5 min and then heated to 60 °C with a heating rate of 5 °C/min.
• the light microscopy experiments are performed on a Nikon Eclipse 50 microscope equipped with an s-poiarizer and hot-stage accessory. A small amount of sebum and the formulation of interest are placed on a microscope slide side-by- side, in contact with each other but not mixed. A cover glass is placed on top. The slide is mounted on a hot stage and the temperature is raised from 25 °C to 35 °C at 2 °C/min and then held at 35 °C. A video is recorded, and photomicrographs are taken. In-Vitro Release Testing i iVRT)
• Release test is performed using a Franz-cell apparatus.
• the tested formulation is placed on a suitable membrane, and a suitable receptor fluid is placed in the receptor chamber.
• the concentration of the active agent in the receptor fluid is measure over time, and the release rate is calculated.
• the surface of the skin samples is cleaned and then tape-stripped 5 times to remove the excess formulation and the upper layers of stratum corneum.
• the skin is then separated into dermis and epidermis by heat treatment.
• the skin samples are extracted and the amount of active agent present in the skin layers is determined by LC-MS/MS. in some experiments, the skin samples are treated with SurgiSeal to extract sebaceous appendages, and the sebaceous appendages, dermis and remaining epidermis are analyzed for the active agent.
• the receiving compartments are sampled at baseline and at 3-, 6-, 9-, and 24-hours following application. At the 24-hour time point the skin is processed as follows:
• Residues of materials are removed from the skin using filter paper.
• the skin is then stripped successively using 20 pieces of adhesive tape "Scotch Magic® Tape", 3M.
• the first piece of adhesive tape is discarded.
• the second through tenth pieces of adhesive tape are transferred into a vial with 3 mL of extraction solution and labeled“Stratum Corneum 1
• the eleventh through twentieth pieces of adhesive tape are transferred into a different vial with 3 ml extraction solution and labeled“Stratum Corneum 2.”
• C. acnes isolates are tested at international Health Management Associates, Inc. (IHMA).
• IHMA international Health Management Associates, Inc.
• a subset is characterized by whole genome sequencing to determine multi-locus sequence type (MLST) and resistance mutations initial minimal inhibitory concentration (MIC) range for quality control strain
• MLST multi-locus sequence type
• MIC minimal inhibitory concentration
• Bacteroides fragilis ATCC 25285 is established.
• Minimal bactericidal concentration (MBC) is determined for clinical strains of C. acnes and B. fragilis.
• Spontaneous resistance frequency to the formulation tested is evaluated by direct plating on antibiotic containing medium after single exposure.
• Infrared spectroscopy model Broker Vertex 70 spectrometer (Broker Optics, Billerica, MA, USA) coupled to a microscope Hyperion 2000IR (Bruker Optics, Billerica, MA, USA) with heating/cooling stage (Linkam, Surrey, UK Linkam T95) connected to a temperature control system (ITS 350; Linkam Scientific Instruments, Ltd.) and a tank of liquid nitrogen is used to measure the infrared spectra. Spectra are detected in transmission mode using a 15x objective and 32 scans in the interval of A from 400 cnr 1 to 4000 cnr 1 with a resolution of 4 cm 1 . The temperature control system is used to maintain the heating and cooling rates of samples. The measurements are obtained using the Opus 7 2 software (Bruker Optics, Billerica, MA, USA).
• a drop of sample is carefully placed on to a barium chloride slide and a cover slide is gently placed on top. Afterwards a heating ramp is set at 5°C/min from 25°C-90°C. The infrared measurements are performed during the heating step (at 25°C, 35°C, 50°C, 60°C, 70°C, 80°C and 90°C).
• an infrared spectroscopy model Bruker Vertex 70 spectrometer (Bruker Optics, Billerica, MA, USA) is coupled to a microscope Hyperion 2000IR (Bruker Optics, Billerica, MA, USA) with heating/cooling stages (Linkam, Surrey, UK Linkam T95) connected to a temperature control system (LTS 350; Linkam Scientific instruments, Ltd.) and a tank of liquid nitrogen.
• Spectra are detected in transmission mode using a 15x objective and performing 32 scans in fhe interval of A from 400 cnr 1 to 4000 cnr 1 with a resolution of 4 cm -1 .
• Samples containing Tmh crystals are sonicated at 50 °C for 15 minutes, then a small aliquot was placed between glass slides and pressed with spatula to attempt to break up any aggregates. The samples are observed by polarized light microscopy at 50 °C with a 2Gx and a 50x objective.
• Aliquots ot formulation samples containing crystals are randomly picked out. Aliquots (e.g., two) are placed on a slide and imaged by light microscopy. The image is captured by a microscope with an image of 845 p x 452 p . A software program calculates the area of the total picture area occupied by each crystal. The percentage area occupied by the crystals is determined with the average of 3 different areas of the image.
• the objective of this study is to characterize local and systemic toxicity, and toxicokinetics of minocycline and adapa!ene foam, along with adapalene as a comparator, when administered via dermal application to Gottingen Minipigs once daily for up to 13 weeks (91 days), and to assess the delayed onset or recovery of any findings following a 28-day non-dosing observation period.
• the study design is provided in table 2 below:
• a Animals in Group 1 are untreated control animals and are treated in the same manner as the treated animals except no test article, vehicle, or control article was administered.
• the animals are removed from the cage, and a detailed clinical examination of each surviving animal is performed weekly during the study. On occasion, clinical observations are recorded at unscheduled intervals.
• the unscheduled examinations performed during the acclimation period are not reported but are maintained in the study file.
• the observations include, but are not limited to, evaluation of the skin, fur, eyes, ears, nose, oral cavity, thorax, abdomen, external genitalia, limbs and feet, respiratory and circulatory effects, autonomic effects such as salivation, and nervous system effects including tremors, convulsions, reactivity to handling, and unusual behavior.
• test site is scored tor erythema/eschar and edema once daily prior to dosing during Week 1 and once weekiy (at 1 hour post-dose on days of dosing) thereafter.
• Body weights for all surviving animals are measured and recorded on the day of receipt, Day -5 (female animals only), prior to randomization (Day -1 ), and weekly during the study. The body weights recorded on the day of receipt and Day -5 are not reported but are maintained in the study file.
• Body weight changes are calculated for animals between each weighing interval.
• a daily qualitative assessment of food intake/appetite is performed for ail surviving animals as part of the twice daily cage side observations. Quantitative food consumption measurements are not conducted.
• Ophthalmic examinations are conducted pretest and prior to the terminal necropsy by an ophthalmologist.
• Electrocardiographic examinations are performed on all surviving animals pretest, pre-dose and 1 to 2 hours post-dose during the last wee k of dosing, and once at the end of the recovery period insofar as possible, care is taken to avoid causing undue excitement of the animals before the recording of electrocardiograms (ECGs) in order to minimize extreme fluctuations or artifacts in these measurements.
• ECGs electrocardiograms
• Standard ECGs (6 Lead) are recorded at 50 mm/sec.
• the RR, PR, and QT intervals, and QRS duration are measured and heart rate is determined. Corrected QT (QTc) interval is calculated using a procedure based on the method described by Fridericia. All tracings are evaluated and reported by a consulting veterinary cardiologist.
• Blood samples (approximately 2 mL) are collected from all surviving animals via the abdominal vena cava through the thoracic inlet for determination of the plasma concentrations of adapalene and minocycline (see Tables 5 and 6). The animals were not fasted prior to blood collection, with the exception of the intervals that coincided with fasting for clinical pathology collections.
• Blood samples are collected in tubes containing K EDTA and placed on wet ice and centrifuged under refrigerated conditions. The resulting plasma is divided into 3 aliquots [100 mI_ in Aliquot 1 [minocycline], 500 pL in Aliquot 2 [adapa!ene], and any remaining plasma in Aliquot 3) in pre-labeled cryoviais. AH aliquots are stored frozen at -60°C to -90°G.
• the TK parameters are determined for adapaiene and minocycline from individual concentration-time data by the Testing Facility.
• Post-mortem study evaluations are performed on animals found dead, euthanized in extremis, or euthanized at the scheduled terminal (Day 92) and recovery necropsies (Day 120).
• Method of Euthansia Euthanasia will be by euthanasia solution administration, under sedation if necessary (e.g. acepromazine and/or Teiazol®), followed by a Testing Facility SOP approved method to ensure death, e.g. exsanguination.
• euthanasia solution administration under sedation if necessary (e.g. acepromazine and/or Teiazol®), followed by a Testing Facility SOP approved method to ensure death, e.g. exsanguination.
• Necropsy examinations are performed under procedures approved by a veterinary pathologist. The animals are examined carefully for external abnormalities including palpable masses. The skin is reflected from a ventral midline incision and subcutaneous masses are identified and correlated with antemortem findings. The abdominal, thoracic, and cranial cavities are examined for abnormalities. The organs are removed, examined, and, where required, placed in fixative. All designated tissues are fixed in neutral buffered formalin, except for the eyes (including the optic nerve) and testes, which are fixed using a modified Davidson’s fixative prior to placement in formalin. Formalin is infused into the lung via the trachea. A full complement of tissues and organs is collected from ail animals.
• Body weights and protocol-designated organ weights are recorded for all surviving animals at the scheduled necropsies and appropriate organ weight ratios are calculated (relative to body and brain weights). Paired organs are weighed together.
• Table 7 defines the set of comparisons used in the statistical analyses described in this section.
• Formulation are prepared as described above.
• the crystals may optionally be concentrated by centrifugation.
• the crystals are isolated by manual breaking of Tmh crystals. Samples containing Tmh crystals are sonicated at 50 °C for 15 minutes, then a small aliquot is placed between glass slides and pressed with spatula to attempt to break up any aggregates. The samples are observed by polarized light microscopy at 50 °C with a 20x and a 5Qx objective.
• a sample is mixed with a solvent in which the crystals are not soluble in approximately a 1 :1 : ratio.
• a solvent acetone/hexane; to separate between crystals
• Microscopic observation and analysis is made at different temperatures and during slow heating, e.g , from 20 to 75°C at 1 °C/min.
• Minocycline HCI and Adapaiene are added to neat soybean oil, neat corn oil or neat safflower oil. The exact amount of Minocycline HCI and Adapaiene are determined for each sample by weighing the active ingredients with analytical balance. The mixtures are placed into glass screw cap vials, tightly closed and exposed for 3 weeks to 50°C temperatures, protected from light.
• Minocycline, Adapalene and their degradation products are determined by HPLC, analyzing the complete samples.
• the extent of degradation of Minocycline and Adapalene is determined for each sample by comparison of amounts of Minocycline HCi and Adapalene recovered in each sample with the weights of Minocycline HCi and Adapalene used in preparation of corresponding samples.
• the content of degradation products is determined by an area percent ratio for each degradation product corresponding to the main peak of the corresponding active ingredient.
• the samples are evaluated for color alterations, as well.
• Step 1 Hydrophobic solvents and solid compounds such as fatty alcohols, fatty acids and waxes are heated with mixing, to a temperature sufficient for a homogenous mixture to be visually observed.
• Step 2 The formulation is cooled down to 35-40 S G, then temperature sensitive components such as cyclomethicone and temperature sensitive active agents such as tetracyclines are added while mixing, until formulation homogeneity is visually observed. If they are to be Included, sensitive active agents such as retinoids are added at 24-28 9 C while mixing until formulation homogeneity is visually observed
• Step 3 The formulation is cooled down to 22-26 e C.
• Step 4 The formulation is mixed (for about 3 up to 24 hours) at 20-24
• Step 5 For gel compositions, the formulation is packaged in suitable containers.
• foamab!e compositions the formulation is packaged in aerosol canisters which are filled, crimped with a valve, and pressurized and mixed with a propellant (e.g., a hydrocarbon gas or gas mixture) as described below.
• a propellant e.g., a hydrocarbon gas or gas mixture
• Each cannister is equipped with an actuator suitable for foam dispensing.
• the canisters or containers are labeled.
• Step 1 Hydrophobic solvents and solid compounds such as fatty alcohols, fatty acids and waxes are heated with mixing, to a temperature sufficient for a homogenous mixture to be visually observed.
• Step 2 The formulation is cooled down to a holding temperature, for example, about 54 9 C and is mixed at this temperature for a holding period, for example, of 4 hours, unless indicated otherwise for a specific example.
• Step 3 The formulation is cooled down to 35-40 S C, then sensitive components such as cyclomethicone and sensitive active agents such as tetracyclines are added while mixing until formulation homogeneity is visually observed
• Step 4 The formulation is cooled down to 24-28 9 C. Sensitive active agents such as retinoids are added (as dispersion in a hydrophobic solvent) under mixing until formulation homogeneity is visually observed.
• Sensitive active agents such as retinoids
• Step 5 The formulation is cooled down to 22-28 S G
• Step 6 The formulation is mixed (for about 3 up to 24 hours) at 20-24
• Step 7 For gel compositions (and pre-foam), the formulation is packaged in suitable containers.
• a non-foam gel for example, it can be packaged in a coated metal tube, which is sealed and capped.
• the formulation is packaged in aerosol canisters which is filled, crimped with a valve and pressurized and mixed with a propellant (e.g., a
• Each cannister is equipped with an actuator suitable for foam dispensing. Lastly, the canisters or containers are labeled.
• the formulation is mixed during one or more or all steps as is needed to ensure the formulation is homogenous.
• Mixing may be a mixing means such as a propeller or stirrer or a homogenizer.
• Each aerosol canister is filled with the pre-foam formulation (“PFF", i.e., foamabie carrier) and crimped with valve, optionally using a vacuum crimping machine.
• PFF pre-foam formulation
• the process of applying a vacuum will cause part of the oxygen present to be eliminated.
• Pressurizing is carried out using a hydrocarbon gas or gas mixture and shaken immediately thereafter. Such a process prepares the foamabie composition as provided herein.
• Each manufacturing process is carried out in a dosed system with purging with nitrogen and mixing under vacuum.
• mixing using high shear or other methods that can input heat or energy into the crystals may be avoided or ameliorated or used only for a relatively short period so that the Tmh crystals are not substantially reduced or eliminated in the composition.
• mixing devices that generate localized heat in the manufacturing system may result in the Tmh crystals melting and or being converted into other crystalline forms such as spherulites.
• Stepl hydroxypropyl methyiceliuiose, xanthan gum and citric acid are added to water at ambient temperature and mixed until fully dissolved. The solution is heated to 60°C while being mixed.
• Step 2 To generate the oil phase caprylic / capric triglyceride is heated to 60° - 7G°C, stearic acid, glyceryl monostearate and cefearefh 20 are added and mixed until excipients fully dissolved.
• Step 3 The oil phase is slowly added to the water phase and aggressively mixed to achieve homogeneous emulsion.
• Step 4 The mixture is cooled down, while being mixed to 35° - 40°C, then glycerin is added. pH is adjusted to 5.0 - 5.5 by either sodium hydroxide or by hydrochloric acid, if needed. The final blend is cooled down to 25°C while being mixed.
• Step 5 For foamable compositions, the formulation is packaged in aerosol canisters which is filled, crimped with a valve and pressurized and mixed with a propellant (e.g., a hydrocarbon gas or gas mixture) as described above.
• a propellant e.g., a hydrocarbon gas or gas mixture
• step 2 addition in step 2 of hydrogenated castor oil (HCO) to the oils in the formulations resulted in a major transition (TM4) appearing at about 69 °G.
• TM4 major transition
• DSC for fhe full formuiation step 9
• HCO transition step 9
• TM4 HCO transition
• Formulations containing either 2% or 1 .2% hydrogenated castor oil (HCO) and active agents comprising a combination of minocycline HCi and adapalene (MCH+ADP) were prepared either by a continuous heating cooling process or a holding process.
• HCO hydrogenated castor oil
• active agents comprising a combination of minocycline HCi and adapalene
• MCH+ADP adapalene
• crystals with plate structures were smaller in formulations prepared by a continuous heating-cooling process (about 12-13 pm 2 on average) compared to those prepared by a holding process (about 15-19 pm 2 on average).
• spherulites (22-23%) and Tmh crystals (30-33%) occupied higher percentages of the area tested for formulations prepared by a continuous heating-cooling process and a holding process, respectively.
• Formulations with 2% HCO showed a similar effect.
• spherulites and small plates were formed and when prepared by a holding process, large plates and Tmh crystals were formed (FIG. 2E).
• TM4 faded over time in a formulation prepared by a continuous heating-cooling process.
• T M 4 remained stable from Day 0 through Day 30 in a formulation prepared by a holding process.
• the increase in temperature to 40 °G also resulted in the appearance of new transitions in the formulation prepared by a holding process.
• it may be possible that the changes observed in the continuous heating- cooling process are delayed In a formulation prepared by a holding process.
• new transitions observed in the formulation prepared by a continuous heating-cooling process at 25 °C were seen in a formulation prepared by a holding process only at 40 °C.
• the holding process "rescues" or holds back the formulation from forming the less stable structures corresponding to transitions T M 3 .I and T M4.I at the lower temperature (25 °C). Keeping formulations at high temperatures is often used to test formulation aging. Thus, these changes that appeared in the DSC only at a higher temperature for a formulation prepared by a holding process may indicate that structural changes may be delayed by the holding process.
• Active and Placebo formulations with 1 .2% or 2% HGO were prepared by either a holding process or a continuous heating-cooling process.
• T M4 enthalpy was higher in ail formulations prepared by a holding process compared to formulations prepared by a continuous heating-cooling process (except tor placebo formulations with 2% HCO that had similar T M 4 enthalpy) (Fig 1 1 )
• This increased enthalpy indicates the structures created in the holding process have stronger bonds, as the energy required to break these bonds is higher than that for the structures created in a continuous heating-cooling process
• Formulations comprising MCH+ADP with 1.2% HCO were prepared by a continuous heating-cooling process and a holding process, kept at 40 °C and analyzed on Day 0 by small angle X-ray scattering.
• the formulation prepared by a holding process had a higher intensity compared to the same formulation prepared by a continuous heating-cooling process.
• the average intensity for the formulation prepared by a holding process was 0.033 cm -1 versus 0 014 cm -1 for the formulation prepared by a continuous heating-cooling process (two repiicates, lower lines).
• the average intensity for a formulation prepared by a holding process was 0.031 cm 1 versus 0.014 cm 1 for a formulation prepared by a continuous heating-cooling process.
• the average intensity of a formulation prepared by a holding process was more than 2 times higher than that of a formulation prepared by a continuous heating-cooling process.
• the higher intensity represents crystals of larger domains, i.e. having a larger crystalline body, and higher order, i.e. the molecular forces participating in the formation of fhe crystalline form are stronger.
• Formulations comprising MCH+ADP with 1.2% HCO were prepared by a continuous heating-cooling process and a holding process, kept at 25 °C and analyzed on Day 0 by wide angle X-ray scattering. As can be seen in FIG. 2M, no differences were observed between the formulations prepared by the different processes. This may indicate that there was no change in the crystalline form, or that any change that did occur was subtle but undetectable by wide-angle X-ray crystallography.
• the amount of light mineral oil in the formulation is adjusted based on the amount of minocycline hydrochloride and/or adapaiene.
• the amount of minocyciine hydrochloride in the formulation is adjusted on the potency of the minocycline hydrochloride.
• the flow point of samples measured at TO was about 33 C for formulation made with continuous or holding process.
• samples stored at 15 days or 30 days at 40°C an increase in the flow point was noticed. See Table 1 1 A.
• the tridimensional network responsible for the product structure may undergo changes at 40°C, with an increase in wax crystal- crystal interactions making a more resistant network.
• samples manufactured using a holding process had a lower flow point than with a continuous process.
• the high- melting TMH crystals generated in the holding process may be more resistant to temperature changes, and less prone to form wax crystal-crystal interactions, resulting in a more f!owabie/shakable and less resistant network, and a lower flow point than that observed with the spheruiite crystals generated in the continuous process.
• Formulation comprising MCH prepared by a continuous heating-cooling process (MCO) and C.
• Oii-in-water emulsion (GIWE) were prepared by the process described in Example 1 A and analyzed by DSC.
• Table 12a and FIG. 3A provide the melting temperature of the sebum in the evaluated samples (determined here as minimum temperature of the melting endotherm and shown as Tm in Tables 12a, and 12b and In Fig. 3A). As can be seen, the Tm value of pure sebum was different from that of mixtures of sebum with the tested formulations (MAH, MCO, and OIWE).
• the amount of light mineral oil in the formulation Is adjusted based on the amount of minocycline hydrochloride and/or adapa!ene.
• formulations prepared by a continuous heating- cooling process [190313N, 190319S) were more rigid and less fluid at 25 °C or 40 °C on Day 15 compared to a formulation prepared by a holding process (190505S). A similar phenomenon was observed on Day 30 (FIG. 4B).
• the improved fluidity of the formulation prepared by a holding process may contribute to the improved shakability of this formulation compared to formulations prepared by a continuous heating-cooling process that were less fluid and less shakable.
• the amount of light mineral oil in the formulation is adjusted based on tne amount of minocycline hydrochloride and/or adapalene.
• shakability was improved in combination formulations (MCH+ADP) prepared by a holding process compared to formulations prepared by a continuous heating -cooling process.
• a combination formulation comprising 2% HCO kept at 25 °C for 30 days was observed to be non- shakable when prepared by a continuous heating-cooling process (19031 3N) and fully shakable when prepared by a holding process (190430R).
• a combination formulation comprising 1 .2% HCO kept at 25 °C for 30 days was moderately-shakable when prepared by a continuous heating-cooling process (19G319S) and fully shakable when prepared by a holding process (190505S).
• Formulations prepared by a holding process that had superior shakability [See Tables 1 1 A-C) surprisingly comprised nonuniform, large and stable crystals that were not observed in formulations prepared by a continuous heating- cooling process. This was unexpected as wide-angle X-ray data showed no apparent change in polymorph (Example 3).
• the stable structures and crystal fingerprint formed by the holding process may be less available to interact with each other and/or with other components of the formulation. This may improve the flowability of the formulation, resulting in a fully shakable formulation.
• the amount of light mineral oil in the formulation is adjusted based on the amount of minocycline hydrochloride and/or adapalene.
• the amount of minocycline hydrochloride in the formulation is adjusted by the potency of the minocycline hydrochloride.
• Step 1 Some of the hydrophobic solvents and solid compounds such as fatty alcohols, fatty acids and waxes (for e.g. soybean oil, HCO, beeswax) were mixed and heated to a temperature sufficient to achieve complete melting.
• Step 2 The formulation was cooled down to about 55-58 E 'C and was mixed under this temperature for a period of 30min.
• Step 3 The formulation was heated to about 65°C and the rest of the hydrophobic solvents and solid compounds was added and mixed until completely melting. The process then continued as described in Example 1 b step 3 onwards.
• Step 1 Some of the hydrophobic solvents and solid compounds such as fatty alcohols, fatty acids and waxes (for example soybean oil, HCO, beeswax) were mixed and heated to a temperature sufficient to achieve complete melting.
• fatty alcohols, fatty acids and waxes for example soybean oil, HCO, beeswax
• Step 2 The formulation was cooled down to about 55-58 5 C and was mixed under this temperature for a period of 30min.
• Step 3 The formulation was heated to about 65°C and the rest of the hydrophobic solvents and solid compounds were added and mixed until completely meiting. The process then continued as described in Example 1 b step 3 onwards.
• a non-shakabie formulation may over time potentially become non-flowable and might lead e.g., to occurrences of blockage of valves and/or nozzles.
• This example presents an alternative continuation process that did not result in crystals with the crystallization fingerprint seen with the holding process discussed above and presents alternative holding processes which produced foamable formulations with less good shakability compared to a formulation prepared by a bolding process.
• Formulations comprising MCH ⁇ ADP with either 1 .2% or 2 % HCO were prepared by different processes.
• an alternative holding process (a) comprising holding at about 52 °C for 4 hours and then heating back to about 85 °C (190512N) resulted in improved shakability as compared to a continuous heating-cooling process, but was less effective than holding at about 54 °C for 4 hours (Table 17, compared to Table 1 1 A in Example 3).
• the alternative holding process resulted in only a moderately- shakable formulation whereas holding at about 54 °C resulted in a fully shakable formulation.
• Such formulations prepared by the continuous process (b) could create, with time, a stiff and hard gel eventually leading to blockage of an aerosol valve.
• Formulations prepared by an alternative holding process holding at about 52 °C and heating to about 65 °C; 190512N) or a process where HCO is added at about 22 °C (19G512S) showed DSC thermograms where faded and new transitions appeared.
• Such DSC thermograms were different from those measured for formulations prepared by a holding process at about 54 °C (FIG. 5). It may be, without being bound by theory, that warming to a higher temperature after a holding period may reduce or eliminate the Tmh crystals,

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